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Hunt AL, Barakat W, Makohon-Moore SC, Hood BL, Conrads KA, Wilson KN, Abulez T, Ogata J, Pienta KJ, Lotan TL, Mani H, Trump DL, Bateman NW, Conrads TP. Histology-resolved proteomics reveals distinct tumor and stromal profiles in low- and high-grade prostate cancer. Clin Proteomics 2025; 22:14. [PMID: 40254573 PMCID: PMC12009531 DOI: 10.1186/s12014-025-09534-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 03/19/2025] [Indexed: 04/22/2025] Open
Abstract
BACKGROUND Prostate cancer is one of the most frequently diagnosed cancers in men. Prostate tumor staging and disease aggressiveness are evaluated based on the Gleason scoring system, which is further used to direct clinical intervention. The Gleason scoring system provides an estimate of tumor aggressiveness through quantitation of the serum level of prostate specific antigen (PSA) and histologic assessment of Grade Group, determined by the Gleason Grade of the tumor specimen. METHODS To improve our understanding of the proteomic characteristics differentiating low- versus high-grade prostate cancer tumors, we performed a deep proteomic characterization of laser microdissected epithelial and stromal subpopulations from surgically resected tissue specimens from patients with Gleason 6 (n = 23 specimens from n = 15 patients) and Gleason 9 (n = 15 specimens from n = 15 patients) prostate cancer via quantitative high-resolution liquid chromatography-tandem mass spectrometry analysis. RESULTS In total, 789 and 295 grade-specific significantly altered proteins were quantified in the tumor epithelium and tumor-involved stroma, respectively. Benign epithelial and stromal populations were not inherently different between Gleason 6 versus Gleason 9 specimens. Notably, 598 proteins were exclusively significantly altered between Gleason 9 (but not Gleason 6) tumor-involved stroma and benign stroma, including several proteins involved in cholesterol biosynthesis and nucleotide metabolism. CONCLUSIONS Proteomic alterations between Gleason 6 versus Gleason 9 were exclusive to the disease microenvironment, observed in both the tumor epithelium and tumor-involved stroma. Further, the molecular alterations measured in the tumor-involved stroma from Gleason 9 cases relative to the benign stroma have unique significance in disease aggressiveness, development, and/or progression. Our data provide supportive evidence of a need for further investigations into targeting stromal reservoirs of cholesterol and/or deoxynucleoside triphosphates in PCa tumors and further highlight the necessity for independent examination of the TME epithelial and stromal compartments.
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Affiliation(s)
- Allison L Hunt
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA, 22003, USA
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Waleed Barakat
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Sasha C Makohon-Moore
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Brian L Hood
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Kelly A Conrads
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Katlin N Wilson
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Tamara Abulez
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Jonathan Ogata
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Kenneth J Pienta
- The Brady Urological Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Haresh Mani
- Department of Pathology, Inova Fairfax Hospital, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Donald L Trump
- Inova Schar Cancer Institute, Inova Health System, 8081 Innovation Park Dr, Fairfax, VA, 22031, USA
| | - Nicholas W Bateman
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, 6720A Rockledge Drive, Suite 100, Bethesda, MD, 20817, USA
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA
| | - Thomas P Conrads
- Women's Health Integrated Research Center, Inova Women's Service Line, Inova Health System, 3289 Woodburn Rd, Annandale, VA, 22003, USA.
- Gynecologic Cancer Center of Excellence and the Women's Health Integrated Research Center, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
- The John P. Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University, 8901 Wisconsin Avenue, Bethesda, MD, 20889, USA.
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Wang Z, Chen H, Liu Y, Zou L, Zhang Z, Yin Z, Mao S, Guo C, Yang B, Wu P, Yao X. Gut microbiota, metabolites, and cytokines in relation to the risk of prostate cancer in the Asian population. Front Oncol 2025; 14:1466190. [PMID: 39882449 PMCID: PMC11774728 DOI: 10.3389/fonc.2024.1466190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
Purpose Studies have shown that gut microbiota is involved in the tumorigenesis and development of prostate cancer. We aimed to perform a comprehensive analysis of causal associations of gut microbiota, metabolites, and cytokines with prostate cancer in the Asian population. Patients and methods Genome-wide association study (GWAS) summary datasets were collected from the public databases. There were 418 bacterial traits, 452 metabolites, 91 cytokines, 5408 cases of prostate cancer from East Asia, and 109,347 controls included. Mendelian randomization (MR) analyses were performed to investigate their causal relationships. Sensitivity analyses were conducted to test the reliability of MR results. Furthermore, the FinnGen database was used to assess the generalizability of our findings based on Asians. Results There were a total of 17 bacterial traits, 28 metabolites (including 2 microbiota-associated metabolites), and 9 cytokines to be significantly associated with prostate cancer in Asians (P < 0.05). Further MR analyses of these positive results indicated that G_Ruminococcaceae UCG014/TNFSF10 axis, G_Anaerofilum/TNFRSF14 axis, G_Erysipelotrichaceae UCG003/TNFSF10 axis, and P_Proteobacteria/cholesterol axis were key signaling pathways involved in the progression of prostate cancer. Notably, G_Ruminococcaceae UCG014/TNFSF10 axis and G_Anaerofilum/TNFRSF14 axis were found to act as protective factors, while the other two signaling axes played a crucial role in promoting the progression of prostate cancer. Sensitivity analyses further confirmed the reliability of our findings. Using the European population as outcome, we further assessed the generalizability of our conclusions and found limited applicability to Europeans. Conclusions We found that there were causal associations of gut microbiota, metabolites, and cytokines with prostate cancer in Asians. The causal effects of gut microbiota on prostate cancer were partially mediated by metabolites and cytokines. These findings might contribute to the development of new therapeutic strategies for prostate cancer.
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Affiliation(s)
- Zhengshi Wang
- Department of Urology, Shanghai Tenth People’s Hospital, Clinical Medical College of Nanjing Medical University, Shanghai, China
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
- Department of Breast and Thyroid Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Haotian Chen
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Yongqiang Liu
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Libin Zou
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Zhijin Zhang
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Zhiqiang Yin
- Department of Breast and Thyroid Surgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- Shanghai Center of Thyroid Diseases, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shiyu Mao
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Changcheng Guo
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Bin Yang
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Pengfei Wu
- Department of Urology, Shanghai Tenth People’s Hospital, Clinical Medical College of Nanjing Medical University, Shanghai, China
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
| | - Xudong Yao
- Department of Urology, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
- Urologic Cancer Institute, School of Medicine, Tongji University, Shanghai, China
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Zhou Z, Huang Z, Zhao Y, Wang Y, Niu Y. Association between low density lipoprotein cholesterol levels and prostate cancer risk in non-hypertensive middle-aged and older American men. Sci Rep 2024; 14:29096. [PMID: 39582086 PMCID: PMC11586403 DOI: 10.1038/s41598-024-80190-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024] Open
Abstract
Often linked with the risk of various diseases, blood low-density lipoprotein cholesterol (LDL-C) levels are typically deemed more favorable when lower. The objective of this investigation is to elucidate the link between blood LDL-C levels and the risk of prostate cancer (PCa) in middle-aged and older men without hypertension in the United States. Utilizing continuous data from the National Health and Nutrition Examination Survey (NHANES) database spanning 2003-2010, a selection of 1,223 non-hypertensive men aged ≥ 40 years was made from a pool of 41,156 participants, ensuring no missing information. Regression analyses were employed to investigate the correlation between blood LDL-C levels and the PCa risk, while identifying potential inflection points indicative of threshold effects. Additionally, we scrutinized the linkage between cholesterol-lowering prescription drug usage and PCa. In our study of 2,224 participants, we found no significant correlation between blood LDL-C levels and the PCa risk after adjusting for confounding variables (Odds Ratio = 0.99; P-value > 0.05). However, upon conducting a subgroup analysis, we discovered a meaningful correlation between lower blood LDL-C levels and an increased PCa risk in the non-hypertensive population (Odds Ratio = 0.99; P-value < 0.05). Meanwhile, we identified a threshold effect and a tipping point at an LDL-C levels of 67 mg/dl. Furthermore, a significant correlation was identified between cholesterol-lowering prescription drug usage and a heightened PCa risk in the non-hypertensive population (Odds Ratio = 18.87; P-value < 0.05; P for interaction < 0.05). Our results indicate that in non-hypertensive middle-aged and older men residing in the United States, lower blood LDL-C levels are not necessarily better and the PCa risk escalates when blood LDL-C levels drop below 67 mg/dl, which may guide early screening and prognosis of PCa in specific populations. This finding calls for further validation via larger sample sizes and a more in-depth analysis of PCa history.
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Affiliation(s)
- Zhen Zhou
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China
| | - Zhicong Huang
- Department of Urology and Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510230, Guangdong, China
| | - Yang Zhao
- Department of Radiology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
| | - Yong Wang
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
| | - Yuanjie Niu
- Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
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Yang G, Cui T, Cao Y, Wang S, Yang X, Enikeev M, He M. Can weight-adjusted waist circumference index become a single anthropometric predictor of prostate-specific antigen concentration? A National Health and Nutrition Examination Survey analysis (2003-2010). J Investig Med 2024; 72:532-540. [PMID: 38644377 DOI: 10.1177/10815589241252356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/23/2024]
Abstract
Recent studies have introduced the weight-adjusted waist circumference index (WWI) as a viable obesity indicator that may better reflect centripetal obesity and its associated risks. In examining the connection between WWI and prostate-specific antigen (PSA), this study leveraged data from the National Health and Nutrition Examination Survey 2003-2010, including 5732 participants. Our initial analysis indicated a significant positive association between WWI and PSA levels. However, subsequent models that adjusted for covariates such as age, race, and a range of metabolic and cardiovascular health-related factors revealed that the strength and significance of this relationship were attenuated. Model 1 showed a highly significant correlation (p < 0.0001). Yet, in Model 2, which accounted for age and race, the association softened (p = 0.0520). Moreover, when a full spectrum of health covariates was included in Model 3, the association was no longer significant (p = 0.9775). These findings suggest that while an unadjusted correlation exists, its potential use as a diagnostic predictor is limited without considering the broader health context. Therefore, it is crucial to review such data with multiple considerations in mind, and extensive attention should be paid to the evaluation of covariates.
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Affiliation(s)
- Guodong Yang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Te Cui
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Yu Cao
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Shuowen Wang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Xinyi Yang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mikhail Enikeev
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Mingze He
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
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Yang G, Cui T, Cao Y, Wang S, Yang X, Enikeev M, He M. Can weight-adjusted waist circumference index become a single anthropometric predictor of prostate-specific antigen concentration? A National Health and Nutrition Examination Survey analysis (2003–2010). J Investig Med 2024; 72:532-540. [DOI: https:/doi.org/10.1177/10815589241252356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/20/2024]
Abstract
Recent studies have introduced the weight-adjusted waist circumference index (WWI) as a viable obesity indicator that may better reflect centripetal obesity and its associated risks. In examining the connection between WWI and prostate-specific antigen (PSA), this study leveraged data from the National Health and Nutrition Examination Survey 2003–2010, including 5732 participants. Our initial analysis indicated a significant positive association between WWI and PSA levels. However, subsequent models that adjusted for covariates such as age, race, and a range of metabolic and cardiovascular health-related factors revealed that the strength and significance of this relationship were attenuated. Model 1 showed a highly significant correlation (p < 0.0001). Yet, in Model 2, which accounted for age and race, the association softened (p = 0.0520). Moreover, when a full spectrum of health covariates was included in Model 3, the association was no longer significant (p = 0.9775). These findings suggest that while an unadjusted correlation exists, its potential use as a diagnostic predictor is limited without considering the broader health context. Therefore, it is crucial to review such data with multiple considerations in mind, and extensive attention should be paid to the evaluation of covariates.
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Affiliation(s)
- Guodong Yang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Te Cui
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Yu Cao
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Shuowen Wang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Xinyi Yang
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | - Mikhail Enikeev
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
| | - Mingze He
- I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
- Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia
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Vialat M, Baabdaty E, Trousson A, Kocer A, Lobaccaro JMA, Baron S, Morel L, de Joussineau C. Cholesterol Dietary Intake and Tumor Cell Homeostasis Drive Early Epithelial Tumorigenesis: A Potential Modelization of Early Prostate Tumorigenesis. Cancers (Basel) 2024; 16:2153. [PMID: 38893271 PMCID: PMC11172085 DOI: 10.3390/cancers16112153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/31/2024] [Accepted: 06/03/2024] [Indexed: 06/21/2024] Open
Abstract
Epidemiological studies point to cholesterol as a possible key factor for both prostate cancer incidence and progression. It could represent a targetable metabolite as the most aggressive tumors also appear to be sensitive to therapies designed to decrease hypercholesterolemia, such as statins. However, it remains unknown whether and how cholesterol, through its dietary uptake and its metabolism, could be important for early tumorigenesis. Oncogene clonal induction in the Drosophila melanogaster accessory gland allows us to reproduce tumorigenesis from initiation to early progression, where tumor cells undergo basal extrusion to form extra-epithelial tumors. Here we show that these tumors accumulate lipids, and especially esterified cholesterol, as in human late carcinogenesis. Interestingly, a high-cholesterol diet has a limited effect on accessory gland tumorigenesis. On the contrary, cell-specific downregulation of cholesterol uptake, intracellular transport, or metabolic response impairs the formation of such tumors. Furthermore, in this context, a high-cholesterol diet suppresses this impairment. Interestingly, expression data from primary prostate cancer tissues indicate an early signature of redirection from cholesterol de novo synthesis to uptake. Taken together, these results reveal that during early tumorigenesis, tumor cells strongly increase their uptake and use of dietary cholesterol to specifically promote the step of basal extrusion. Hence, these results suggest the mechanism by which a reduction in dietary cholesterol could lower the risk and slow down the progression of prostate cancer.
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Affiliation(s)
- Marine Vialat
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Elissa Baabdaty
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Amalia Trousson
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Ayhan Kocer
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Jean-Marc A. Lobaccaro
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Silvère Baron
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Laurent Morel
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
| | - Cyrille de Joussineau
- GReD, CNRS UMR6293, Inserm U1103, Université Clermont Auvergne, 28 Place Henri Dunant, BP38, F63001 Clermont-Ferrand, France; (M.V.); (E.B.); (A.T.); (A.K.); (J.-M.A.L.); (S.B.); (L.M.)
- Groupe Cancer Clermont Auvergne, F63000 Clermont-Ferrand, France
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Göbel A, Pählig S, Motz A, Breining D, Traikov S, Hofbauer LC, Rachner TD. Overcoming statin resistance in prostate cancer cells by targeting the 3-hydroxy-3-methylglutaryl-CoA-reductase. Biochem Biophys Res Commun 2024; 710:149841. [PMID: 38588613 DOI: 10.1016/j.bbrc.2024.149841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 03/14/2024] [Accepted: 03/26/2024] [Indexed: 04/10/2024]
Abstract
Prostate cancer is the most prevalent malignancy in men. While diagnostic and therapeutic interventions have substantially improved in recent years, disease relapse, treatment resistance, and metastasis remain significant contributors to prostate cancer-related mortality. Therefore, novel therapeutic approaches are needed. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway which plays an essential role in cholesterol homeostasis. Numerous preclinical studies have provided evidence for the pleiotropic antitumor effects of statins. However, results from clinical studies remain controversial and have shown substantial benefits to even no effects on human malignancies including prostate cancer. Potential statin resistance mechanisms of tumor cells may account for such discrepancies. In our study, we treated human prostate cancer cell lines (PC3, C4-2B, DU-145, LNCaP) with simvastatin, atorvastatin, and rosuvastatin. PC3 cells demonstrated high statin sensitivity, resulting in a significant loss of vitality and clonogenic potential (up to - 70%; p < 0.001) along with an activation of caspases (up to 4-fold; p < 0.001). In contrast, C4-2B and DU-145 cells were statin-resistant. Statin treatment induced a restorative feedback in statin-resistant C4-2B and DU-145 cells through upregulation of the HMGCR gene and protein expression (up to 3-folds; p < 0.01) and its transcription factor sterol-regulatory element binding protein 2 (SREBP-2). This feedback was absent in PC3 cells. Blocking the feedback using HMGCR-specific small-interfering (si)RNA, the SREBP-2 activation inhibitor dipyridamole or the HMGCR degrader SR12813 abolished statin resistance in C4-2B and DU-145 and induced significant activation of caspases by statin treatment (up to 10-fold; p < 0.001). Consistently, long-term treatment with sublethal concentrations of simvastatin established a stable statin resistance of a PC3SIM subclone accompanied by a significant upregulation of both baseline as well as post-statin HMGCR protein (gene expression up to 70-fold; p < 0.001). Importantly, the statin-resistant phenotype of PC3SIM cells was reversible by HMGCR-specific siRNA and dipyridamole. Our investigations reveal a key role of a restorative feedback driven by the HMGCR/SREBP-2 axis in statin resistance mechanisms of prostate cancer cells.
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Affiliation(s)
- Andy Göbel
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Sophie Pählig
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Anja Motz
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Dorit Breining
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Sofia Traikov
- Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany
| | - Lorenz C Hofbauer
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tilman D Rachner
- Mildred Scheel Early Career Center, Division of Endocrinology and Metabolic Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; Center for Healthy Ageing, Department of Medicine III, Technische Universität Dresden, Dresden, Germany; German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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8
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Guo J, Chen S, Zhang Y, Liu J, Jiang L, Hu L, Yao K, Yu Y, Chen X. Cholesterol metabolism: physiological regulation and diseases. MedComm (Beijing) 2024; 5:e476. [PMID: 38405060 PMCID: PMC10893558 DOI: 10.1002/mco2.476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 01/09/2024] [Accepted: 01/12/2024] [Indexed: 02/27/2024] Open
Abstract
Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.
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Affiliation(s)
- Jiarui Guo
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Silong Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ying Zhang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Jinxia Liu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Luyang Jiang
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Lidan Hu
- National Clinical Research Center for Child HealthThe Children's HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Ke Yao
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Yibo Yu
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
| | - Xiangjun Chen
- Eye Center of the Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
- Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang ProvinceChina
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9
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Liu H, Shui IM, Keum N, Shen X, Wu K, Clinton SK, Cao Y, Song M, Zhang X, Platz EA, Giovannucci EL. Plasma total cholesterol concentration and risk of higher-grade prostate cancer: A nested case-control study and a dose-response meta-analysis. Int J Cancer 2023; 153:1337-1346. [PMID: 37306155 PMCID: PMC10527248 DOI: 10.1002/ijc.34621] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/13/2023]
Abstract
Our previous publication found an increased risk of higher-grade (Gleason sum ≥7) prostate cancer for men with high total cholesterol concentration (≥200 mg/dl) in the Health Professionals Follow-up Study (HPFS). With additional 568 prostate cancer cases, we are now able to investigate this association in more detail. For the nested case-control study, we included 1260 men newly diagnosed with prostate cancer between 1993 and 2004, and 1328 controls. For the meta-analyses, 23 articles studied the relationship between total cholesterol level and prostate cancer incidence were included. Logistic regression models and dose-response meta-analysis were performed. An increased risk of higher-grade (Gleason sum ≥4 + 3) prostate cancer for high vs low quartile of total cholesterol level was observed in the HPFS (ORmultivariable = 1.56; 95% CI = 1.01-2.40). This finding was compatible with the association noted in the meta-analysis of highest vs lowest group of total cholesterol level, which suggested a moderately increased risk of higher-grade prostate cancer (Pooled RR =1.21; 95%CI: 1.11-1.32). Moreover, the dose-response meta-analysis indicated that an increased risk of higher-grade prostate cancer occurred primarily at total cholesterol levels ≥200 mg/dl, where the RR was 1.04 (95%CI: 1.01-1.08) per 20 mg/dl increase in total cholesterol level. However, total cholesterol concentration was not associated with the risk of prostate cancer overall either in the HPFS or in the meta-analysis. Our primary finding, as well as the result of the meta-analysis suggested a modest increased risk of higher-grade prostate cancer, at total cholesterol concentrations exceeding 200 mg/dl.
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Affiliation(s)
- Hui Liu
- Central Lab, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310058, China
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
| | | | - NaNa Keum
- Department of Food Science and Biotechnology, Dongguk University, Goyang, 10326, Korea
| | - Xudan Shen
- Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, China
| | - Kana Wu
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
| | - Steven K. Clinton
- Division of Public Health Sciences, Division of Medical Oncology, The James Cancer Hospital and The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
| | - Yin Cao
- Department of Surgery, Washington University School of Medicine, St Louis, MO, 63110, USA
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Xuehong Zhang
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Elizabeth A. Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, 21205, USA
| | - Edward L. Giovannucci
- Department of Nutrition, Harvard School of Public Health, Boston, MA, 02115, USA
- Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA
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10
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Wanjari UR, Mukherjee AG, Gopalakrishnan AV, Murali R, Dey A, Vellingiri B, Ganesan R. Role of Metabolism and Metabolic Pathways in Prostate Cancer. Metabolites 2023; 13:183. [PMID: 36837801 PMCID: PMC9962346 DOI: 10.3390/metabo13020183] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 01/21/2023] [Accepted: 01/21/2023] [Indexed: 01/27/2023] Open
Abstract
Prostate cancer (PCa) is the common cause of death in men. The pathophysiological factors contributing to PCa are not well known. PCa cells gain a protective mechanism via abnormal lipid signaling and metabolism. PCa cells modify their metabolism in response to an excessive intake of nutrients to facilitate advancement. Metabolic syndrome (MetS) is inextricably linked to the carcinogenic progression of PCa, which heightens the severity of the disease. It is hypothesized that changes in the metabolism of the mitochondria contribute to the onset of PCa. The studies of particular alterations in the progress of PCa are best accomplished by examining the metabolome of prostate tissue. Due to the inconsistent findings written initially, additional epidemiological research is required to identify whether or not MetS is an aspect of PCa. There is a correlation between several risk factors and the progression of PCa, one of which is MetS. The metabolic symbiosis between PCa cells and the tumor milieu and how this type of crosstalk may aid in the development of PCa is portrayed in this work. This review focuses on in-depth analysis and evaluation of the metabolic changes that occur within PCa, and also aims to assess the effect of metabolic abnormalities on the aggressiveness status and metabolism of PCa.
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Affiliation(s)
- Uddesh Ramesh Wanjari
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Anirban Goutam Mukherjee
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Reshma Murali
- Department of Biomedical Sciences, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632014, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, Kolkata 700073, India
| | - Balachandar Vellingiri
- Stem Cell and Regenerative Medicine/Translational Research, Department of Zoology, School of Basic Sciences, Central University of Punjab (CUPB), Bathinda 151401, India
| | - Raja Ganesan
- Institute for Liver and Digestive Diseases, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea
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11
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Relationship between 4-Hydroxynonenal (4-HNE) as Systemic Biomarker of Lipid Peroxidation and Metabolomic Profiling of Patients with Prostate Cancer. Biomolecules 2023; 13:biom13010145. [PMID: 36671530 PMCID: PMC9855859 DOI: 10.3390/biom13010145] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/29/2022] [Accepted: 01/04/2023] [Indexed: 01/13/2023] Open
Abstract
An oxidative degradation product of the polyunsaturated fatty acids, 4-hydroxynonenal (4-HNE), is of particular interest in cancer research due to its concentration-dependent pleiotropic activities affecting cellular antioxidants, metabolism, and growth control. Although an increase in oxidative stress and lipid peroxidation was already associated with prostate cancer progression a few decades ago, the knowledge of the involvement of 4-HNE in prostate cancer tumorigenesis is limited. This study investigated the appearance of 4-HNE-protein adducts in prostate cancer tissue by immunohistochemistry using a genuine 4-HNE monoclonal antibody. Plasma samples of the same patients and samples of the healthy controls were also analyzed for the presence of 4-HNE-protein adducts, followed by metabolic profiling using LC-ESI-QTOF-MS and GC-EI-Q-MS. Finally, the analysis of the metabolic pathways affected by 4-HNE was performed. The obtained results revealed the absence of 4-HNE-protein adducts in prostate carcinoma tissue but increased 4-HNE-protein levels in the plasma of these patients. Metabolomics revealed a positive association of different long-chain and medium-chain fatty acids with the presence of prostate cancer. Furthermore, while linoleic acid positively correlated with the levels of 4-HNE-protein adducts in the blood of healthy men, no correlation was obtained for cancer patients indicating altered lipid metabolism in this case. The metabolic pathway of unsaturated fatty acids biosynthesis emerged as significantly affected by 4-HNE. Overall, this is the first study linking 4-HNE adduction to plasma proteins with specific alterations in the plasma metabolome of prostate cancer patients. This study revealed that increased 4-HNE plasma protein adducts could modulate the unsaturated fatty acids biosynthesis pathway. It is yet to be determined if this is a direct result of 4-HNE or whether they are produced by the same underlying mechanisms. Further mechanistic studies are needed to grasp the biological significance of the observed changes in prostate cancer tumorigenesis.
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12
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Fang S, Yarmolinsky J, Gill D, Bull CJ, Perks CM, the PRACTICAL Consortium, Davey Smith G, Gaunt TR, Richardson TG. Association between genetically proxied PCSK9 inhibition and prostate cancer risk: A Mendelian randomisation study. PLoS Med 2023; 20:e1003988. [PMID: 36595504 PMCID: PMC9810198 DOI: 10.1371/journal.pmed.1003988] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 11/18/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Prostate cancer (PrCa) is the second most prevalent malignancy in men worldwide. Observational studies have linked the use of low-density lipoprotein cholesterol (LDL-c) lowering therapies with reduced risk of PrCa, which may potentially be attributable to confounding factors. In this study, we performed a drug target Mendelian randomisation (MR) analysis to evaluate the association of genetically proxied inhibition of LDL-c-lowering drug targets on risk of PrCa. METHODS AND FINDINGS Single-nucleotide polymorphisms (SNPs) associated with LDL-c (P < 5 × 10-8) from the Global Lipids Genetics Consortium genome-wide association study (GWAS) (N = 1,320,016) and located in and around the HMGCR, NPC1L1, and PCSK9 genes were used to proxy the therapeutic inhibition of these targets. Summary-level data regarding the risk of total, advanced, and early-onset PrCa were obtained from the PRACTICAL consortium. Validation analyses were performed using genetic instruments from an LDL-c GWAS conducted on male UK Biobank participants of European ancestry (N = 201,678), as well as instruments selected based on liver-derived gene expression and circulation plasma levels of targets. We also investigated whether putative mediators may play a role in findings for traits previously implicated in PrCa risk (i.e., lipoprotein a (Lp(a)), body mass index (BMI), and testosterone). Applying two-sample MR using the inverse-variance weighted approach provided strong evidence supporting an effect of genetically proxied inhibition of PCSK9 (equivalent to a standard deviation (SD) reduction in LDL-c) on lower risk of total PrCa (odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76 to 0.96, P = 9.15 × 10-3) and early-onset PrCa (OR = 0.70, 95% CI = 0.52 to 0.95, P = 0.023). Genetically proxied HMGCR inhibition provided a similar central effect estimate on PrCa risk, although with a wider 95% CI (OR = 0.83, 95% CI = 0.62 to 1.13, P = 0.244), whereas genetically proxied NPC1L1 inhibition had an effect on higher PrCa risk with a 95% CI that likewise included the null (OR = 1.34, 95% CI = 0.87 to 2.04, P = 0.180). Analyses using male-stratified instruments provided consistent results. Secondary MR analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.90 per SD reduction in PCSK9 expression, 95% CI = 0.86 to 0.95, P = 5.50 × 10-5) and circulating plasma levels of PCSK9 (OR = 0.93 per SD reduction in PCSK9 protein levels, 95% CI = 0.87 to 0.997, P = 0.04) on PrCa risk. Colocalization analyses identified strong evidence (posterior probability (PPA) = 81.3%) of a shared genetic variant (rs553741) between liver-derived PCSK9 expression and PrCa risk, whereas weak evidence was found for HMGCR (PPA = 0.33%) and NPC1L1 expression (PPA = 0.38%). Moreover, genetically proxied PCSK9 inhibition was strongly associated with Lp(a) levels (Beta = -0.08, 95% CI = -0.12 to -0.05, P = 1.00 × 10-5), but not BMI or testosterone, indicating a possible role for Lp(a) in the biological mechanism underlying the association between PCSK9 and PrCa. Notably, we emphasise that our estimates are based on a lifelong exposure that makes direct comparisons with trial results challenging. CONCLUSIONS Our study supports a strong association between genetically proxied inhibition of PCSK9 and a lower risk of total and early-onset PrCa, potentially through an alternative mechanism other than the on-target effect on LDL-c. Further evidence from clinical studies is needed to confirm this finding as well as the putative mediatory role of Lp(a).
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Affiliation(s)
- Si Fang
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
| | - James Yarmolinsky
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
| | - Dipender Gill
- Chief Scientific Advisor Office, Research and Early Development, Novo Nordisk, Copenhagen, Denmark
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
| | - Caroline J. Bull
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
- Bristol Renal, Bristol Heart Institute, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- IGF & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, Learning & Research Building, Southmead Hospital, Bristol, United Kingdom
| | - Claire M. Perks
- IGF & Metabolic Endocrinology Group, Translational Health Sciences, Bristol Medical School, Learning & Research Building, Southmead Hospital, Bristol, United Kingdom
| | | | - George Davey Smith
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
| | - Tom R. Gaunt
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
| | - Tom G. Richardson
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom
- Medical Research Council (MRC) Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
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13
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Association of Statin Use with the Risk of Incident Prostate Cancer: A Meta-Analysis and Systematic Review. JOURNAL OF ONCOLOGY 2022; 2022:7827821. [PMID: 36561541 PMCID: PMC9767737 DOI: 10.1155/2022/7827821] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 11/12/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022]
Abstract
Background With the growth and aging of population, the incidence of prostate cancer will increase year by year, which is bound to bring greater economic burden to the society. There has been greater interest in the anticancer effects of statin in recent years. It is controversial whether statin use is associated with the risk of prostate cancer (PCa). Thus, we conducted a meta-analysis and systematic review to explore the effects of statin use and their duration and cumulative dose on the overall incidence of PCa. Method The study was conducted according to the latest guidelines for PRISMA 2020. We searched PubMed and other databases for studies about the association of statin use with the risk of incident prostate cancer between January 1, 1990, and April 11, 2022. Two independent researchers extracted data and evaluated the quality of the studies. R x64 4.1.2 and random-effects model were used for data statistics. Relative risk (RR) and odds ratio (OR) effective values with a 95% confidence interval (95% CI) were used to assess the main results. Results The results of 6 RCT and 26 cohort studies showed that statins did not significantly associate with the incidence of PCa (RR = 0.94, 95% CI: 0.82-1.08). The similar results were obtained from 9 case-control studies (OR = 1.03, 95% CI: 0.99-1.07). However, statins were associated with a lower risk of Pca (RR = 0.44, 95% CI: 0.28-0.70) when the cumulative defined daily dose (cDDD) was high. Using statins for more than five years could be associated with a reduced incidence of Pca (RR = 0.47, 95% CI: 0.23-0.97). There was a significant heterogeneity in these studies (RCT and cohort study: I 2 = 98%, P < 0.01; case-control study: I 2 = 72%, P < 0.01). Conclusion We concluded that statins had a neutral association with the overall risk of PCa. High cDDD and long duration were associated with a lower risk of PCa.
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14
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Clark EH, Ahmed ST, Chang E, Chiao EY, White DL. Can statins lessen the burden of virus mediated cancers? Infect Agent Cancer 2022; 17:47. [PMID: 36058947 PMCID: PMC9441070 DOI: 10.1186/s13027-022-00460-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world's cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers. MAIN BODY Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV. CONCLUSION Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk.
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Affiliation(s)
- Eva H Clark
- Section of Infectious Diseases, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
- Section of Pediatric Tropical Medicine, Baylor College of Medicin, Feigin Building Suite 550, Houston, TX, 77030, USA.
| | - Sarah T Ahmed
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elaine Chang
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Elizabeth Y Chiao
- Departments of Epidemiology and General Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Donna L White
- Center for Innovation, Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey VA Medical Center, Houston, TX, USA
- Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, TX, USA
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15
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Wei C, Tian L, Jia B, Wang M, Xiong M, Hu B, Deng C, Hou Y, Hou T, Yang X, Chen Z. Association between Serum Triglycerides and Prostate Specific Antigen (PSA) among U.S. Males: National Health and Nutrition Examination Survey (NHANES), 2003-2010. Nutrients 2022; 14:nu14071325. [PMID: 35405939 PMCID: PMC9002993 DOI: 10.3390/nu14071325] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/10/2022] [Accepted: 03/21/2022] [Indexed: 01/10/2023] Open
Abstract
(1) Background: Increasing evidence indicates that lipid metabolism may influence the concentration of prostate-specific antigen (PSA). However, the association between triglycerides and PSA remains unclear and complicated. Hence, we evaluated the correlation between triglycerides and PSA based on the U.S. National Health and Nutrition Examination Survey (NHANES) database. (2) Methods: A total of 2910 participants out of 41,156 participants fit into our study after conducting the screening from the 2003 to 2010 NHANES survey. Serum triglycerides were the independent variable of our study, and PSA was the dependent variable; (3) Results: In our study, the average age of chosen participants was 59.7 years (±12.7). After adjusting for covariates, the result indicated that for each additional unit of serum triglyceride (mg/dL), the PSA concentrations were reduced by 0.0043 ng/mL (−0.0082, −0.0005) with a statistical difference. Furthermore, we used machine learning of the XGBoost model to determine the relative importance of selected variables as well as constructed a smooth curve based on the fully adjusted model to investigate the possible linear relationship between the triglyceride and PSA concentrations. (4) Conclusions: The serum triglyceride is independently and negatively correlated with PSA among American males, which may make it hard to detect asymptomatic prostate cancer and diagnose at an advance stage with higher triglycerides due to detection bias.
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Affiliation(s)
- Chengcheng Wei
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Liang Tian
- Department of Urology, Wuhan Red Cross Hospital, Wuhan 430015, China;
| | - Bo Jia
- People’s Hospital of Dongxihu District, Wuhan 430040, China; (B.J.); (B.H.)
| | - Miao Wang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Ming Xiong
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Bo Hu
- People’s Hospital of Dongxihu District, Wuhan 430040, China; (B.J.); (B.H.)
| | - Changqi Deng
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Yaxin Hou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Teng Hou
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Xiong Yang
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
| | - Zhaohui Chen
- Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China; (C.W.); (M.W.); (M.X.); (C.D.); (Y.H.); (T.H.); (X.Y.)
- Correspondence:
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16
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Nakayama H, Sekine Y, Oka D, Miyazawa Y, Arai S, Koike H, Matsui H, Shibata Y, Suzuki K. Combination therapy with novel androgen receptor antagonists and statin for castration-resistant prostate cancer. Prostate 2022; 82:314-322. [PMID: 34843630 DOI: 10.1002/pros.24274] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 02/19/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC. METHODS LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide). RESULTS The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes. CONCLUSIONS Simvastatin alters the expression of many genes involved in the cell cycle in CRPC cells. Thus, the combination of novel AR antagonists (darolutamide) and simvastatin can potentially affect CRPC growth through both androgen-dependent and androgen-independent mechanisms.
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Affiliation(s)
- Hiroshi Nakayama
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yoshitaka Sekine
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Daisuke Oka
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yoshiyuki Miyazawa
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Seiji Arai
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Hidekazu Koike
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Hiroshi Matsui
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Yasuhiro Shibata
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
| | - Kazuhiro Suzuki
- Department of Urology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan
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Vettenranta A, Murtola TJ, Raitanen J, Raittinen P, Talala K, Taari K, Stenman UH, Tammela TLJ, Auvinen A. Outcomes of Screening for Prostate Cancer Among Men Who Use Statins. JAMA Oncol 2021; 8:61-68. [PMID: 34817559 DOI: 10.1001/jamaoncol.2021.5672] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Importance Prostate-specific antigen (PSA) screening for prostate cancer has resulted in a slight reduction in prostate cancer mortality but also a concomitant overdiagnosis of low-risk tumors. Prostate-specific antigen levels are affected by use of cholesterol-lowering statin drugs, but the association of statin use with PSA screening performance is unknown. Objective To investigate whether statin use was associated with outcomes of a randomized PSA-based prostate cancer screening intervention. Design, Setting, and Participants This post hoc subgroup analysis of a cohort from a population-based randomized clinical trial used data from the population-based Finnish Randomized Study of Prostate Cancer Screening, which randomized men to PSA screening or routine care from March 1, 1996, to December 31, 1999, with follow-up continuing until December 31, 2015. The population included all men aged 55 to 67 years at baseline and residing in the Tampere or Helsinki districts of Finland. Information on statin purchases from 1996 to 2009 was obtained from a national prescription registry. Eligible men were identified from the population registry of Finland. Prevalent prostate cancer cases at baseline were excluded. Data were analyzed from January 1, 2019 to March 31, 2021. Interventions Three invitations for PSA screening at 4-year intervals from 1996 to 2007 vs routine care. Main Outcomes and Measures Risk for prostate cancer overall, high-risk disease, and prostate cancer mortality in the screening group vs the control group as an intention-to-treat analysis. The analysis was stratified by statin use. Results The study comprised 78 606 men (median age, 59 years [range, 55-67 years]) with statin purchase data available. Although PSA screening was associated with increased prostate cancer incidence among statin nonusers (screening vs control, 11.2 vs 8.6 per 1000 person-years); rate ratio [RR], 1.31; 95% CI, 1.24-1.38), no similar increase in incidence was observed among statin users (6.9 vs 5.9 per 1000 person-years; RR, 1.02; 95% CI, 0.95-1.10; P < .001 for interaction). Incidence of low-risk (Gleason score 6) and localized tumors was lower among statin users, whereas detection of tumors with a Gleason score of 8 to 10 was similar. Screening was associated with a lower incidence of metastatic tumors regardless of statin use. Conclusion and Relevance In this post hoc subgroup analysis of a cohort from a population-based randomized clinical trial, PSA screening among statin users was associated with a decreased incidence of advanced prostate cancer that was similar among statin nonusers, but with less increase in detection of low-grade localized tumors in statin users than in nonusers. These findings suggest that statin use does not materially compromise benefits of PSA-based screening.
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Affiliation(s)
- Arla Vettenranta
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland
| | - Teemu J Murtola
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.,Tays Cancer Centre, Department of Urology, Tampere, Finland
| | - Jani Raitanen
- Tampere University, Faculty of Social Sciences, Tampere, Finland.,Urho Kaleva Kekkonen Institute for Health Promotion Research, Tampere, Finland
| | - Paavo Raittinen
- Aalto University, Department of Mathematics and Systems Analysis, Helsinki, Finland
| | | | - Kimmo Taari
- Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ulf-Håkan Stenman
- Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Department of Clinical Chemistry, University of Helsinki, Helsinki, Finland
| | - Teuvo L J Tammela
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.,Tays Cancer Centre, Department of Urology, Tampere, Finland
| | - Anssi Auvinen
- Tampere University, Faculty of Medicine and Health Technology, Tampere, Finland.,Tampere University, Faculty of Social Sciences, Tampere, Finland
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18
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Pandey M, Cuddihy G, Gordon JA, Cox ME, Wasan KM. Inhibition of Scavenger Receptor Class B Type 1 (SR-B1) Expression and Activity as a Potential Novel Target to Disrupt Cholesterol Availability in Castration-Resistant Prostate Cancer. Pharmaceutics 2021; 13:1509. [PMID: 34575583 PMCID: PMC8467449 DOI: 10.3390/pharmaceutics13091509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 02/07/2023] Open
Abstract
There have been several studies that have linked elevated scavenger receptor class b type 1 (SR-B1) expression and activity to the development and progression of castration-resistant prostate cancer (CRPC). SR-B1 facilitates the influx of cholesterol to the cell from lipoproteins in systemic circulation. This influx of cholesterol may be important for many cellular functions, including the synthesis of androgens. Castration-resistant prostate cancer tumors can synthesize androgens de novo to supplement the loss of exogenous sources often induced by androgen deprivation therapy. Silencing of SR-B1 may impact the ability of prostate cancer cells, particularly those of the castration-resistant state, to maintain the intracellular supply of androgens by removing a supply of cholesterol. SR-B1 expression is elevated in CRPC models and has been linked to poor survival of patients. The overarching belief has been that cholesterol modulation, through either synthesis or uptake inhibition, will impact essential signaling processes, impeding the proliferation of prostate cancer. The reduction in cellular cholesterol availability can impede prostate cancer proliferation through both decreased steroid synthesis and steroid-independent mechanisms, providing a potential therapeutic target for the treatment of prostate cancer. In this article, we discuss and highlight the work on SR-B1 as a potential novel drug target for CRPC management.
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Affiliation(s)
- Mitali Pandey
- Department of Urological Sciences, Faculty of Medicine, University of British Columbia, Vancouver Prostate Centre, Vancouver, BC V6T 1Z3, Canada; (M.P.); (M.E.C.)
| | - Grace Cuddihy
- College of Pharmacy and Nutrition, University of Saskatchewan, 104 Clinic Place, Saskatoon, SK S7N 2Z4, Canada;
| | - Jacob A. Gordon
- Oncology Bioscience, Oncology R&D, AstraZeneca, Boston, MA 02451, USA;
| | - Michael E. Cox
- Department of Urological Sciences, Faculty of Medicine, University of British Columbia, Vancouver Prostate Centre, Vancouver, BC V6T 1Z3, Canada; (M.P.); (M.E.C.)
| | - Kishor M. Wasan
- Department of Urological Sciences, Faculty of Medicine, University of British Columbia, Vancouver Prostate Centre, Vancouver, BC V6T 1Z3, Canada; (M.P.); (M.E.C.)
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19
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Li Y, Cheng X, Zhu JL, Luo WW, Xiang HR, Zhang QZ, Peng WX. Effect of Statins on the Risk of Different Stages of Prostate Cancer: A Meta-Analysis. Urol Int 2021; 106:869-877. [PMID: 34518476 DOI: 10.1159/000518164] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/22/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION The aim of this article was to investigate the relationship between statins and the risk of different stages or grades of prostate cancer. METHODS A comprehensive literature search was performed for articles published until December 18, 2020, on the PubMed, Embase, and the Cochrane Library databases. The pooled relative risk (RR) and 95% confidence interval (CI) were then analyzed using the STATA.16.0 software. RESULTS A total of 588,055 patients from 14 studies were included in the analysis. We found that the use of statins expressed a significant correlation with a lower risk of advanced prostate cancer (RR = 0.81, 95% CI: 0.73-0.91; RR = 0.86, 95% CI: 0.75-0.99, respectively). However, no evidence suggested that the use of statins was beneficial for the prevention of localized prostate cancer incidence. Similarly, the pooled results also revealed no association between the use of statins and the risk of high-grade and low-grade prostate cancer. CONCLUSION It has been found that the use of statins is associated with a lower risk of advanced prostate cancer but was not related to the risk of localized, low-grade, or high-grade prostate cancer.
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Affiliation(s)
- Yun Li
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuan Cheng
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Jia-Lian Zhu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Wen Luo
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Huai-Rong Xiang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qi-Zhi Zhang
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Wen-Xing Peng
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
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20
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Garrido MM, Marta JC, Ribeiro RM, Pinheiro LC, Guimarães JT. Serum lipids and prostate cancer. J Clin Lab Anal 2021; 35:e23705. [PMID: 33724557 PMCID: PMC8059719 DOI: 10.1002/jcla.23705] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Conflicting results are found in the literature relating serum lipids levels and prostate cancer. Some results imply a relationship between them; others contradict this association. The purpose of this study was to investigate a possible association between serum lipids levels and prostate cancer, at time of diagnosis. METHODS We measured serum levels of total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides in 237 patients submitted to a prostate biopsy, with PSA between 2 and 10 ng/ml. Patients without cancer at biopsy were used as controls, and the others were considered as cases. No information about lipid-lowering therapy, including statins, was available neither in cases nor in controls. Cases were divided into risk groups, according to the disease severity, based on staging. Lipids levels were compared between groups, using parametric and nonparametric tests. Logistic regression analysis and odds ratios were calculated. RESULTS LDL and total cholesterol levels were lower in patients with cancer, with the difference being statistically significant for LDL cholesterol (p = 0.010) and borderline for total cholesterol (p = 0.050). No significant differences were found between the several risk groups. Odds ratios for low LDL cholesterol (<130 mg/dl) and low total cholesterol (<200 mg/dl), with prostate cancer as the outcome, were 1.983 and 1.703, respectively. There were no significant differences between cases and controls for the other lipids. CONCLUSION Lower LDL cholesterol (<130 mg/dl) and lower total cholesterol (<200 mg/dl) serum levels seem to associate with prostate cancer, at time of diagnosis.
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Affiliation(s)
- Manuel M. Garrido
- Department of Clinical PathologyCentral Lisbon University Hospital Center & Department of Laboratory Medicine, School of Medicine, University of LisbonLisbonPortugal
| | - José C. Marta
- Department of Clinical PathologyCentral Lisbon University Hospital CenterLisbonPortugal
| | - Ruy M. Ribeiro
- Biomathematics LaboratorySchool of Medicine, University of LisbonLisbonPortugal
| | - Luís C. Pinheiro
- Department of UrologyCentral Lisbon University Hospital Center & Department of Urology, Nova Medical SchoolLisbonPortugal
| | - João T. Guimarães
- Department of Clinical PathologySao Joao University Hospital Center & Department of Biomedicine, School of Medicine & Institute of Public Health, University of PortoPortoPortugal
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21
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Guo YY, Peng XL, Zhan N, Tian S, Li J, Dong WG. Development and validation a simple model for identify malignant ascites. Int J Med Sci 2021; 18:1966-1974. [PMID: 33850466 PMCID: PMC8040393 DOI: 10.7150/ijms.53743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 02/01/2021] [Indexed: 12/29/2022] Open
Abstract
The differential diagnosis of benign ascites and malignant ascites is incredibly challenging for clinicians. This research aimed to develop a user-friendly predictive model to discriminate malignant ascites from non-malignant ascites through easy-to-obtain clinical parameters. All patients with new-onset ascites fluid were recruited from January 2014 to December 2018. The medical records of 317 patients with ascites for various reasons in Renmin Hospital of Wuhan University were collected and reviewed retrospectively. Thirty-six parameters were included and selected using univariate logistic regression, multivariate logistic regression, and receiver operating characteristic (ROC) curve analyses to establish a mathematical model for differential diagnosis, and its diagnostic performance was validated in the other groups. Age, cholesterol, hypersensitivity C-reactive protein (hs-CRP) in serum, ascitic fluid adenosine deaminase (AF ADA), ascitic fluid lactate dehydrogenase (AF LDH) involvement in a 5-marker model. With a cut-off level of 0.83, the sensitivity, specificity, accuracy, and area under the ROC of the model for identifying malignant ascites in the development dataset were 84.7%, 88.8%, 87.6%, and 0.874 (95% confidence interval [CI], 0.822-0.926), respectively, and 80.9%, 82.6%, 81.5%, and 0.863 (95% CI,0.817-0.913) in the validation dataset, respectively. The diagnostic model has a similar high diagnostic performance in both the development and validation datasets. The mathematical diagnostic model based on the five markers is a user-friendly method to differentiate malignant ascites from benign ascites with high efficiency.
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Affiliation(s)
- Ying-Yun Guo
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Xiu-Lan Peng
- Department of Oncology, The Fifth Hospital of Wuhan, Wuhan, Hubei, 430050, China
| | - Na Zhan
- Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Shan Tian
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
| | - Jiao Li
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, China
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22
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Chen PY, Hsieh MJ, Liao YH, Lin YC, Hou YT. Liver-on-a-chip platform to study anticancer effect of statin and its metabolites. Biochem Eng J 2021. [DOI: 10.1016/j.bej.2020.107831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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23
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Prabhu N, Kapur N, Catalona W, Leikin R, Helenowski I, Jovanovich B, Gurley M, Okwuosa TM, Kuzel TM. Statin use and risk of prostate cancer biochemical recurrence after radical prostatectomy. Urol Oncol 2020; 39:130.e9-130.e15. [PMID: 33132024 DOI: 10.1016/j.urolonc.2020.09.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 09/21/2020] [Accepted: 09/26/2020] [Indexed: 10/23/2022]
Abstract
BACKGROUND Multiple studies have investigated the role of statins in prostate cancer (CaP), the leading cause of cancer related death in men. Retrospective cohort studies investigating the correlation between statin use and biochemical recurrence free (BCRF) survival in men with CaP have been inconclusive. OBJECTIVES In the largest reported surgical cohort to date, we investigated the effect of statin therapy on BCRF and overall survival in patients with CaP who have undergone radical prostatectomy (RP). PATIENTS AND METHODS We performed a retrospective analysis of men (n = 3,088) participating in the NCI funded Specialized Program of Research Excellence (SPORE) in CaP at Northwestern University (NM) in Chicago, Illinois. Patients were treated with RP between 2002 and 2015. Patients in the statin users group received treatment within 2 years prior to or subsequent to RP. Wilcoxon rank-sum and Fisher's exact tests were used to compare age, race, Gleason score, clinical staging, and pathological stage between statin users and nonstatin users. RESULTS The analysis identified 1,222 statin users and 1,865 nonusers (mean age 71 years, 92% Caucasian). After a median follow-up time of 49.0 months, the 5-year BCRF survival rate was 93.3% (95% confidence interval [CI]: 91.9-94.8%) among statin users and 88.6% (95% CI: 87.1%-90%) among nonusers (log-rank P< 0.001). After 10 years, the progression-free survival (PFS) was 91.7% (95% CI: 90.1%-93.3%) among statin users and 86.5% (95% CI: 84.4%-88.2%) among nonusers (log-rank P< 0.001). CONCLUSIONS Extended follow-up data in this large surgical cohort show statin use improves BCRF but not overall survival in RP patients.
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Affiliation(s)
- Nicole Prabhu
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL
| | - Navina Kapur
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL.
| | | | - Robin Leikin
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
| | - Irene Helenowski
- Department of Preventative Medicine, Northwestern University, Chicago, IL
| | - Borko Jovanovich
- Department of Preventative Medicine, Northwestern University, Chicago, IL
| | - Michael Gurley
- Northwestern University Clinical and Translational Sciences Institute, Chicago, IL
| | - Tochi M Okwuosa
- Division of Cardiology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL
| | - Timothy M Kuzel
- Division of Hematology/Oncology/Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, IL
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24
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Van Rompay MI, Solomon KR, Nickel JC, Ranganathan G, Kantoff PW, McKinlay JB. Prostate cancer incidence and mortality among men using statins and non-statin lipid-lowering medications. Eur J Cancer 2019; 112:118-126. [PMID: 30850323 PMCID: PMC6501826 DOI: 10.1016/j.ejca.2018.11.033] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/15/2018] [Accepted: 11/27/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Statins have demonstrated protection against aggressive/late-stage and/or lethal prostate cancer (PC), but prior studies are limited by small populations, short follow-up and unequal health-care access. Research has not demonstrated that non-statin lipid-lowering medications (NSLLMs) provide a similar benefit, which would support a cholesterol-based mechanism. We sought to rigorously test the hypothesis that cholesterol-lowering drugs affect PC incidence and severity. METHODS A retrospective cohort study was conducted by abstracting prescription and health service records for 249,986 Saskatchewan men aged ≥40 years between January 1, 1990 and December 31, 2014 and comparing first-time statin and NSLLM users with age-matched non-users and glaucoma medication (GM) users for PC incidence, metastases at diagnosis and PC mortality using Cox proportional hazards regression. RESULTS In comparing statin users to non-users, a weak association was detected with increased PC incidence (hazard ratio [HR] 1.07, 95% confidence interval [CI]: 1.02-1.12) that disappeared when compared with GM users. Substantial protective associations were observed between statin use and metastatic PC and PC mortality (HRs 0.69, 95% CI: 0.61-0.79 and 0.73, 95% CI: 0.66-0.81, respectively), which were stronger when compared with GM use (HRs 0.52, 95% CI: 0.40-0.68 and 0.51, 95% CI: 0.41-0.63, respectively). Similar associations were found for NSLLM versus GM for metastatic PC (HR 0.57, 95% CI: 0.41-0.79) and PC mortality (HR 0.66, 95% CI: 0.51-0.85). CONCLUSIONS Our analyses provide one of the more comprehensive findings to date that statins may reduce risk of metastatic PC and PC mortality, and the first to demonstrate that NSLLM have similar effects, supporting a cholesterol-based mechanism.
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Affiliation(s)
| | - Keith R Solomon
- Department of Orthopaedic Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA; Department of Urology, Boston Children's Hospital, Boston, MA 02115, USA.
| | - J Curtis Nickel
- Department of Urology, Queen's University, Kingston, ON, Canada.
| | | | - Philip W Kantoff
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - John B McKinlay
- HealthCore-NERI, 480 Pleasant Street, Watertown, MA 02472, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
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25
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Di Francesco S, Robuffo I, Caruso M, Giambuzzi G, Ferri D, Militello A, Toniato E. Metabolic Alterations, Aggressive Hormone-Naïve Prostate Cancer and Cardiovascular Disease: A Complex Relationship. ACTA ACUST UNITED AC 2019; 55:medicina55030062. [PMID: 30866568 PMCID: PMC6473682 DOI: 10.3390/medicina55030062] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/30/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023]
Abstract
Background: Epidemiological studies suggest a possible relationship between metabolic alterations, cardiovascular disease and aggressive prostate cancer, however, no clear consensus has been reached. Objective: The aim of the study was to analyze the recent literature and summarize our experience on the association between metabolic disorders, aggressive hormone-naïve prostate cancer and cardiovascular disease. Method: We identified relevant papers by searching in electronic databases such as Scopus, Life Science Journals, and Index Medicus/Medline. Moreover, we showed our experience on the reciprocal relationship between metabolic alterations and aggressive prostate cancer, without the influence of hormone therapy, as well the role of coronary and carotid vasculopathy in advanced prostate carcinoma. Results: Prostate cancer cells have an altered metabolic homeostatic control linked to an increased aggressivity and cancer mortality. The absence of discrimination of risk factors as obesity, systemic arterial hypertension, diabetes mellitus, dyslipidemia and inaccurate selection of vascular diseases as coronary and carotid damage at initial diagnosis of prostate cancer could explain the opposite results in the literature. Systemic inflammation and oxidative stress associated with metabolic alterations and cardiovascular disease can also contribute to prostate cancer progression and increased tumor aggressivity. Conclusions: Metabolic alterations and cardiovascular disease influence aggressive and metastatic prostate cancer. Therefore, a careful evaluation of obesity, diabetes mellitus, dyslipidemia, systemic arterial hypertension, together with a careful evaluation of cardiovascular status, in particular coronary and carotid vascular disease, should be carried out after an initial diagnosis of prostatic carcinoma.
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Affiliation(s)
- Simona Di Francesco
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Iole Robuffo
- Institute of Molecular Genetics, National Research Council, Section of Chieti, 66100 Chieti, Italy.
| | - Marika Caruso
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
| | - Giulia Giambuzzi
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Deborah Ferri
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
| | - Andrea Militello
- Department of Urological, Biomedical and Translational Sciences, Federiciana University, 87100 Cosenza, Italy.
- Urology and Andrology Section, Villa Immacolata Hospital, 01100 Viterbo, Italy.
| | - Elena Toniato
- Department of Medical and Oral Sciences and Biotechnologies, G. D'Annunzio University of Chieti-Pescara, 66100 Chieti, Italy.
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Anderson-Carter I, Posielski N, Liou JI, Khemees TA, Downs TM, Abel EJ, Jarrard DF, Richards KA. The impact of statins in combination with androgen deprivation therapyin patients with advanced prostate cancer: A large observational study. Urol Oncol 2019; 37:130-137. [PMID: 30528885 PMCID: PMC6919968 DOI: 10.1016/j.urolonc.2018.11.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 11/09/2018] [Accepted: 11/19/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Statins are thought to possess antineoplastic properties related to their effect on cell proliferation and steroidogenesis. Progression to castrate resistant prostate cancer (CaP) includes de-regulation of androgen synthesis suggesting a role for statins in this setting. Our goal was to assess the role of statin use on oncologic outcomes in patients with advanced CaP being treated with androgen deprivation therapy (ADT). METHODS The national VA database was used to identify all men diagnosed with CaP who were treated with ADT for at least 6 months between 2000 and 2008 with follow-up through May 2016. Our cohort was stratified based on statin use of at least 6 months duration during the same time. Multivariable Cox proportional hazards analyses with inverse propensity score weighted (IPSW) adjustment were calculated to assess for primary outcomes of CaP-specific survival (CSS), overall survival (OS) and skeletal related events (SREs). RESULTS A total of 87,346 patients on ADT were included in the study cohort, 53,360 patients used statins and 33,986 did not. Statin users were younger in age (median 73 vs. 76, P < 0.001), more likely to have a higher Charlson comorbidity index (CCI) >3 (3.1% vs. 2.5%, P < 0.001) and more likely to have a high grade (Gleason score 8-10) cancer (12.3% vs. 10.9%, P < 0.001). Statin users had longer OS (median 6.5 vs. 4.0 years P < 0.001) and decreased death from CaP (5-year CSS 94.0% vs. 87.3%, P < 0.001). Statin use was also associated with longer time to a SRE (median 5.9 vs. 3.7 years, P < 0.001). On multivariable Cox proportional hazards analysis with inverse propensity score weighted, statin use was an independent predictor of improved OS (hazard ratio [HR] 0.66, confidence interval [CI] 0.63-0.68; P < 0.001), CSS (HR 0.56, 95% CI 0.53-0.60; P < 0.001), and SREs (HR 0.64, 95%CI 0.59-0.71; P < 0.001) when controlling for age, race, Charlson comorbidity index, prostate-specific antigen, and Gleason score. CONCLUSION The use of statins in men on ADT for CaP is associated with improved CSS and OS. Statins are inexpensive, well-tolerated medications that offer a promising adjunct to ADT, but require further prospective studies.
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Affiliation(s)
| | - Natasza Posielski
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
| | - Jinn-ing Liou
- The University of Wisconsin-Madison, Department of Medicine, Madison, WI
| | - Tariq A. Khemees
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
| | - Tracy M. Downs
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
| | - E. Jason Abel
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
| | - David F. Jarrard
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
| | - Kyle A. Richards
- The University of Wisconsin-Madison, Department of Urology, Madison, WI
- William S. Middleton Memorial Veterans Hospital, Department of Surgery, Section of Urology, Madison, WI
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Abstract
Obesity leads to many diseases including hypercholesterolemia, type-2 diabetes, hypertension, cardiovascular disease, and cancer. It is the fastest-growing lethal disease in the Western and developing countries. The link between obesity and cancer is relatively underappreciated among the general population. Obesity represents the number one risk factor for type-2 diabetes and a considerable body of epidemiological studies supports the relationship between type-2 diabetes and many cancers. In this review, we examine the obesity-type-2-diabetes-cancer relationships from a mechanistic perspective, and where appropriate, we highlight potential pharmaceutical and dietary interventions.
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Affiliation(s)
- Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA
- Graduate Program in Biology, City University of New York Graduate Center, New York, USA
| | - Casey L. Rosen
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA
| | - Melissa Aslan
- Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli Turkey
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28
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Murtola TJ, Kasurinen TVJ, Talala K, Taari K, Tammela TLJ, Auvinen A. Serum cholesterol and prostate cancer risk in the Finnish randomized study of screening for prostate cancer. Prostate Cancer Prostatic Dis 2018; 22:66-76. [PMID: 30214034 DOI: 10.1038/s41391-018-0087-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/26/2018] [Accepted: 05/16/2018] [Indexed: 01/18/2023]
Abstract
BACKGROUND Hypercholesterolemia has been associated with advanced stage prostate cancer (PCa), but the role of lipid parameters such as HDL and triglycerides is unclear. We examined PCa risk by lipid parameters in a population nested within the Finnish Randomized Study of Screening for Prostate Cancer (FinRSPC). METHODS Cholesterol measurements were available on 17,696 men. During the 17-year median follow-up, 2404 PCa cases were diagnosed. Cox regression model was used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI) for overall PCa risk and stratified by Gleason grade and tumor stage. We compared normolipidemic and hyperlipidemic men on four cholesterol parameters total cholesterol (TC), HDL, LDL, and triglycerides (TG), analyzed as time-dependent variables. RESULTS TC in the highest tertile (above 5.1 mmol/l) and LDL above 3 mmol/l were associated with increased risk of Gleason 8-10 cancer (HR 1.42, 95% CI 1.04-1.95 and HR 1.38, 95% CI 1.02-1.86, respectively). Further, overall PCa risk was elevated in the 3-year lag time analysis by TC in the highest two tertiles (HR 1.27, 95% CI 1.05-1.54 for TC above 4.4 mmol/l, and HR 1.26, 95% CI 1.05-1.51 for TC above 5.1 mmol/l) and HDL in the highest tertile (HR 1.33, 95% CI 1.08-1.64) and above 1 mmol/l (HR 1.29, 95% CI 1.01-1.65). In contrast, TC in the highest tertile was associated with a decreased risk of PCa with 20-year lag time. The risk associations for overall PCa grew stronger with added lag time but were observed only in the FinRSPC control arm. Statin use did not modify the risk association. CONCLUSIONS Hypercholesterolemia may increase overall PCa risk in short-term, inverse risk association was observed with 20-years' time lag. Similar risk increase of overall PCa was also observed for elevated HDL, conflicting with previous findings on the subject.
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Affiliation(s)
- Teemu J Murtola
- Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland. .,Department of Urology, Tampere University Hospital, Tampere, Finland.
| | - Tatu V J Kasurinen
- Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
| | | | - Kimmo Taari
- Department of Urology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Teuvo L J Tammela
- Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland.,Department of Urology, Tampere University Hospital, Tampere, Finland
| | - Anssi Auvinen
- Faculty of Social Sciences, University of Tampere, Tampere, Finland
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29
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Allott EH, Masko EM, Freedland AR, Macias E, Pelton K, Solomon KR, Mostaghel EA, Thomas GV, Pizzo SV, Freeman MR, Freedland SJ. Serum cholesterol levels and tumor growth in a PTEN-null transgenic mouse model of prostate cancer. Prostate Cancer Prostatic Dis 2018; 21:196-203. [PMID: 29795142 PMCID: PMC6026483 DOI: 10.1038/s41391-018-0045-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 02/06/2018] [Accepted: 02/07/2018] [Indexed: 12/28/2022]
Abstract
Background Some, but not all, epidemiologic evidence supports a role for cholesterol, the precursor for steroid hormone synthesis, in prostate cancer. Using a PTEN-null transgenic mouse model of prostate cancer, we tested the effect of modifying serum cholesterol levels on prostate tumor development and growth. We hypothesized that serum cholesterol reduction would lower tumor androgens and slow prostate cancer growth. Methods PTENloxP/loxP-Cre+ mice consuming ad libitum high fat, high cholesterol diets (40% fat, 1.25% cholesterol) were randomized after weaning to receive the cholesterol uptake inhibitor, ezetimibe (30 mg/kg/day), or no intervention, and sacrificed at 2, 3 or 4 months of age. Serum cholesterol and testosterone were measured by ELISA and intraprostatic androgens by mass spectrometry. Prostate histology was graded, and proliferation and apoptosis in tumor epithelium and stroma was assessed by Ki67 and TUNEL, respectively. Results Ezetimibe-treated mice had lower serum cholesterol at 4 months (p=0.031). Serum cholesterol was positively correlated with prostate weight (p=0.033) and tumor epithelial proliferation (p=0.069), and negatively correlated with tumor epithelial apoptosis (p=0.004). Serum cholesterol was unrelated to body weight (p=0.195). Tumor stromal cell proliferation was reduced in the ezetimibe group (p=0.010). Increased serum cholesterol at 4 months was associated with elevated intraprostatic DHEA, testosterone and androstenedione (p=0.043, p=0.074, p=0.031, respectively). However, cholesterol reduction did not significantly affect adenocarcinoma development at 2, 3 or 4 months of age (0%, 78%, 100% in ezetimibe-treated vs. 0%, 80%, 100% in mice not receiving ezetimibe). Conclusions Though serum cholesterol reduction did not significantly affect the rate of adenocarcinoma development in the PTEN-null transgenic mouse model of prostate cancer, it lowered intraprostatic androgens and slowed tumor growth. These findings support a role for serum cholesterol in promoting prostate cancer growth, potentially via enhanced tumor androgen signaling, and may provide new insight into cholesterol-lowering interventions for prostate cancer treatment.
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Affiliation(s)
- Emma H Allott
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Elizabeth M Masko
- Department of Surgery, Duke University Medical Center, Durham, NC, USA
| | - Alexis R Freedland
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Everardo Macias
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Kristine Pelton
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Keith R Solomon
- The Urological Diseases Research Center, Boston Children's Hospital, Boston, MA, USA.,Applied Photophysics, Beverly, MA, USA
| | - Elahe A Mostaghel
- Division of Oncology, Department of Medicine, University of Washington, Seattle, WA, USA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - George V Thomas
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.,Pathology and Laboratory Medicine, Oregon Health and Science University, Portland, OR, USA
| | - Salvatore V Pizzo
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Michael R Freeman
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Stephen J Freedland
- Department of Surgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. .,Division of Urology, Veterans Affairs Medical Center, Durham, NC, USA.
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30
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Schnoeller TJ, Jentzmik F, Schrader AJ, Steinestel J. Influence of serum cholesterol level and statin treatment on prostate cancer aggressiveness. Oncotarget 2018; 8:47110-47120. [PMID: 28445145 PMCID: PMC5564548 DOI: 10.18632/oncotarget.16943] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 03/14/2017] [Indexed: 01/19/2023] Open
Abstract
Both cholesterol levels and the use of statins have been described to influence the development and prognosis of prostate cancer (PC). In this retrospective, cross-sectional analysis of consecutive cases from a tertiary referral center we evaluated an association between hypercholesterolemia (≥5.0mmol/l), the use of statins, and advanced/aggressive PC in 767 men with histologically confirmed, clinically localized PC awaiting radical prostatectomy. We found that patients with HCE (n=287, 37.4%) had a significantly higher incidence of poorly differentiated PC (Gleason score ≥7b, 81.1% vs. 4.9%), advanced local tumor stage (≥pT3, 57.7% vs. 22.2%), and nodal involvement (19.8% vs. 1.6%). Multivariate logistic regression analysis identified hypercholesterolemia as a risk factor for aggressive and/or advanced PC (OR 2.01, p<0.001) whereas statin intake showed an odds ratio of 0.49 (p=0.005) indicating a negative association with high-risk PC. Despite a limited number of patients using statins (~9.5%), adjusted and weighed multivariate logistic regression models revealed that preoperative hypercholesterolemia is associated with a diagnosis of high-risk PC which is negatively influenced by statin intake.
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Affiliation(s)
| | - Florian Jentzmik
- Department of Urology, Ulm University Medical Center, Ulm, Germany.,Department of Urology, St. Elisabeth Hospital, Ravensburg, Germany
| | - Andres J Schrader
- Department of Urology, Muenster University Medical Center, Muenster, Germany
| | - Julie Steinestel
- Department of Urology, Muenster University Medical Center, Muenster, Germany
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31
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Chen YA, Lin YJ, Lin CL, Lin HJ, Wu HS, Hsu HY, Sun YC, Wu HY, Lai CH, Kao CH. Simvastatin Therapy for Drug Repositioning to Reduce the Risk of Prostate Cancer Mortality in Patients With Hyperlipidemia. Front Pharmacol 2018; 9:225. [PMID: 29623039 PMCID: PMC5874326 DOI: 10.3389/fphar.2018.00225] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 02/27/2018] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer (PCa) is one of the most commonly diagnosed cancers in the western world, and the mortality rate from PCa in Asia has been increasing recently. Statins are potent inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase and are commonly used for treating hyperlipidemia, with beneficial effects for cardiovascular disease and they also exhibit anti-cancer activity. However, the protective effects of statins against PCa are controversial. In this study, we investigated the effect of two types of statins (simvastatin and lovastatin) and the mortality rate of PCa patients by using the Taiwan National Health Insurance Research Database (NHIRD). A total of 15,264 PCa patients with hyperlipidemia records and medical claims from the Registry of Catastrophic Illness were enrolled. The patients were divided into two cohorts based on their statin use before the diagnosis of PCa: statin users (n = 1,827) and non-statin users (n = 1,826). The results showed that patients who used statins exhibited a significantly reduced risk of mortality from PCa [adjusted hazard ratio (HR) = 0.84, 95% CI = 0.73–0.97]. Analysis of the cumulative defined daily dose (DDD) indicated that patients who were prescribed simvastatin ≥ 180 DDD had a dramatically decreased risk of death from PCa (adjusted HR = 0.63; 95% CI = 0.51–0.77). This population-based cohort study demonstrated that statin use significantly decreased the mortality of PCa patients, and that this risk was inversely associated with the cumulative DDD of simvastatin therapy. The results of this study revealed that statins may be used for drug repositioning and in the development of a feasible approach to prevent death from PCa.
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Affiliation(s)
- Yu-An Chen
- Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Ying-Ju Lin
- Department of Medical Research, School of Chinese Medicine, China Medical University and Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.,Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
| | - Hwai-Jeng Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang-Ho Hospital, New Taipei City, Taiwan
| | - Hua-Shan Wu
- Department of Medical Research, School of Chinese Medicine, China Medical University and Hospital, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan
| | - Hui-Ying Hsu
- Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Yu-Chen Sun
- Department of Laboratory Medicine, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Hui-Yu Wu
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chih-Ho Lai
- Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan.,Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.,Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Linkou, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Basic Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.,Department of Nuclear Medicine, PET Center, China Medical University Hospital, Taichung, Taiwan
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32
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Serum cholesterol and risk of high-grade prostate cancer: results from the REDUCE study. Prostate Cancer Prostatic Dis 2017; 21:252-259. [PMID: 29282360 PMCID: PMC6021229 DOI: 10.1038/s41391-017-0030-9] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2017] [Accepted: 11/13/2017] [Indexed: 12/17/2022]
Abstract
Background Epidemiologic evidence for a serum cholesterol-prostate cancer link is mixed. Prostate-specific antigen (PSA) is positively correlated with cholesterol, potentially increasing PSA-driven biopsy recommendations in men with high cholesterol, though biopsy compliance may be lower in men with comorbid conditions. These potential biases may affect PSA-driven biopsy rates and subsequent prostate cancer detection in men with high serum cholesterol. Our objective was to test the association between serum cholesterol and prostate cancer risk in men receiving PSA-independent, study-mandated prostate biopsies. Methods We conducted a post-hoc analysis of data from 4,974 non-statin users in REDUCE, a randomized trial in men with elevated PSA and a negative baseline biopsy. Men underwent 2- and 4-year trial-mandated prostate biopsies. Associations between baseline serum levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and prostate cancer risk, overall and by Gleason grade (<7 vs. ≥7), were examined using multivariable logistic regression. Results High total serum cholesterol was associated with an increased risk of high-grade prostate cancer diagnosis (ORper10mg/dl 1.05; 95% CI 1.00-1.09; p=0.048), but cholesterol was unrelated to either overall or low-grade prostate cancer risk (p-values>0.185). There was no association between serum LDL and overall, low- or high-grade prostate cancer risk (p-values>0.137). In contrast, elevated serum HDL was associated with increased risk of both overall (ORper10mg/dl 1.08; 95% CI 1.01-1.16; p=0.033) and high-grade prostate cancer (ORper10mg/dl 1.14; 95% CI 1.01-1.28; p=0.034). Conclusions In REDUCE, where all men received PSA-independent, trial-mandated biopsies thus ensuring complete prostate cancer ascertainment, high total serum cholesterol and high HDL were associated with increased risk of high-grade prostate cancer, supporting a cholesterol-prostate cancer link.
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33
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Miller DR, Ingersoll MA, Chou YW, Wakefield CB, Tu Y, Lin FF, Chaney WG, Lin MF. Anti-Androgen Abiraterone Acetate Improves the Therapeutic Efficacy of Statins on Castration-Resistant Prostate Cancer Cells. JOURNAL OF ONCOLOGY RESEARCH AND THERAPY 2017; 3:139. [PMID: 31328181 PMCID: PMC6641547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The treatment of castration-resistant (CR) prostate cancer (PCa) is limited. A sub-population of CR PCa tumors can synthesize androgens for intracrine androgen receptor (AR) activation, thus targeting androgen biosynthesis could be an effective therapeutic option for these patients. We determined that androgen biosynthesis inhibitors simvastatin, atorvastatin, and ketoconazole directly inhibit growth, migration, and colony formation of LNCaP C-81 cells, which exhibit de novo androgen biosynthesis, with simvastatin being the most effective. Importantly, in combination treatments, statins specifically enhanced growth suppression with added effects by anti-androgen abiraterone acetate on the CR PCa cells. Thus, statins can be used in conjunction with abiraterone acetate to enhance anti-androgen therapy for CR PCa.
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Affiliation(s)
- Dannah R. Miller
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Matthew A. Ingersoll
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yu-wei Chou
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- BioBank/Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan, China
| | - C. Brent Wakefield
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Section of Urological Surgery, School of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yaping Tu
- Department of Pharmacology, Creighton University School of Medicine, Omaha, NE, USA
| | - Fen-Fen Lin
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Human Genetic Laboratory, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA
| | - William G. Chaney
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Ming-Fong Lin
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Section of Urological Surgery, School of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
- Eppley Institute for Cancer Research, University of Nebraska, Medical Center, Omaha, NE, USA
- College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, China
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34
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Mucci LA, Kantoff PW. Is the Evidence Sufficient to Recommend Statins for All Men With Prostate Cancer? J Clin Oncol 2017; 35:3272-3274. [DOI: 10.1200/jco.2017.74.7915] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Lorelei A. Mucci
- Lorelei A. Mucci, Harvard TH Chan School of Public Health, Boston, MA; and Philip W. Kantoff, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Philip W. Kantoff
- Lorelei A. Mucci, Harvard TH Chan School of Public Health, Boston, MA; and Philip W. Kantoff, Memorial Sloan Kettering Cancer Center, New York, NY
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35
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Effects of cholesterol, C-reactive protein, and interleukin-6 on prostate cancer risk in a population of African ancestry. Cancer Causes Control 2017; 28:1313-1321. [DOI: 10.1007/s10552-017-0945-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2017] [Accepted: 08/16/2017] [Indexed: 12/14/2022]
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36
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Masko EM, Alfaqih MA, Solomon KR, Barry WT, Newgard CB, Muehlbauer MJ, Valilis NA, Phillips TE, Poulton SH, Freedland AR, Sun S, Dambal SK, Sanders SE, Macias E, Freeman MR, Dewhirst MW, Pizzo SV, Freedland SJ. Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. Prostate 2017; 77:446-457. [PMID: 27900797 PMCID: PMC5822711 DOI: 10.1002/pros.23282] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 11/04/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Epidemiologic data suggest cholesterol-lowering drugs may prevent the progression of prostate cancer, but not the incidence of the disease. However, the association of combination therapy in cholesterol reduction on prostate or any cancer is unclear. In this study, we compared the effects of the cholesterol lowering drugs simvastatin and ezetimibe alone or in combination on the growth of LAPC-4 prostate cancer in vivo xenografts. METHODS Proliferation assays were conducted by MTS solution and assessed by Student's t-test. 90 male nude mice were placed on a high-cholesterol Western-diet for 7 days then injected subcutaneously with 1 × 105 LAPC-4 cells. Two weeks post-injection, mice were randomized to control, 11 mg/kg/day simvastatin, 30 mg/kg ezetimibe, or the combination and sacrificed 42 days post-randomization. We used a generalized linear model with the predictor variables of treatment, time, and treatment by time (i.e., interaction term) with tumor volume as the outcome variable. Total serum and tumor cholesterol were measured. Tumoral RNA was extracted and cDNA synthesized from 1 ug of total RNA for quantitative real-time PCR. RESULTS Simvastatin directly reduced in vitro prostate cell proliferation in a dose-dependent, cell line-specific manner, but ezetimibe had no effect. In vivo, low continuous dosing of ezetimibe, delivered by food, or simvastatin, delivered via an osmotic pump had no effect on tumor growth compared to control mice. In contrast, dual treatment of simvastatin and ezetimibe accelerated tumor growth. Ezetimibe significantly lowered serum cholesterol by 15%, while simvastatin had no effect. Ezetimibe treatment resulted in higher tumor cholesterol. A sixfold induction of low density lipoprotein receptor mRNA was observed in ezetimibe and the combination with simvastatin versus control tumors. CONCLUSIONS Systemic cholesterol lowering by ezetimibe did not slow tumor growth, nor did the cholesterol independent effects of simvastatin and the combined treatment increased tumor growth. Despite lower serum cholesterol, tumors from ezetimibe treated mice had higher levels of cholesterol. This study suggests that induction of low density lipoprotein receptor is a possible mechanism of resistance that prostate tumors use to counteract the therapeutic effects of lowering serum cholesterol. Prostate 77:446-457, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Elizabeth M. Masko
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Mahmoud A. Alfaqih
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Keith R. Solomon
- Department of Orthopedic Surgery, Harvard Medical School, Boston, Massachusetts
| | - William T. Barry
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - Christopher B. Newgard
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina
| | - Michael J. Muehlbauer
- Sarah W. Stedman Nutrition and Metabolism Center, Duke University, Durham, North Carolina
| | - Nikolaos A. Valilis
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Tameika E. Phillips
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Susan H. Poulton
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
| | - Alexis R. Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephanie Sun
- Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina
| | - Shweta K. Dambal
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Sergio E. Sanders
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Everardo Macias
- Division of Urologic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Michael R. Freeman
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mark W. Dewhirst
- Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina
| | - Salvatore V. Pizzo
- Department of Pathology, Duke University Medical Center, Durham, North Carolina
| | - Stephen J. Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California
- Department of Surgery, Durham Veterans Administration Hospital, Durham, North Carolina
- Correspondence to: Dr. Stephen Freedland, Division of Urology, Department of Surgery, Cedars Sinai Medical Center, 8635 West 3rd Street Suite 1070W, Los Angeles, CA 90048.
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Davies JT, Delfino SF, Feinberg CE, Johnson MF, Nappi VL, Olinger JT, Schwab AP, Swanson HI. Current and Emerging Uses of Statins in Clinical Therapeutics: A Review. Lipid Insights 2016; 9:13-29. [PMID: 27867302 PMCID: PMC5110224 DOI: 10.4137/lpi.s37450] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/20/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023] Open
Abstract
Statins, a class of cholesterol-lowering medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, are commonly administered to treat atherosclerotic cardiovascular disease. Statin use may expand considerably given its potential for treating an array of cholesterol-independent diseases. However, the lack of conclusive evidence supporting these emerging therapeutic uses of statins brings to the fore a number of unanswered questions including uncertainties regarding patient-to-patient variability in response to statins, the most appropriate statin to be used for the desired effect, and the efficacy of statins in treating cholesterol-independent diseases. In this review, the adverse effects, costs, and drug–drug and drug–food interactions associated with statin use are presented. Furthermore, we discuss the pleiotropic effects associated with statins with regard to the onset and progression of autoimmune and inflammatory diseases, cancer, neurodegenerative disorders, strokes, bacterial infections, and human immunodeficiency virus. Understanding these issues will improve the prognosis of patients who are administered statins and potentially expand our ability to treat a wide variety of diseases.
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Affiliation(s)
- Jonathan T Davies
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Spencer F Delfino
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Chad E Feinberg
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Meghan F Johnson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Veronica L Nappi
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Joshua T Olinger
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Anthony P Schwab
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Hollie I Swanson
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
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Abstract
An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate- cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell-based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed.
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Heir T, Falk RS, Robsahm TE, Sandvik L, Erikssen J, Tretli S. Cholesterol and prostate cancer risk: a long-term prospective cohort study. BMC Cancer 2016; 16:643. [PMID: 27535659 PMCID: PMC4989293 DOI: 10.1186/s12885-016-2691-5] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Accepted: 08/03/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Few studies have taken risk of competing events into account when examining the relationship between cholesterol and prostate cancer incidence, and few studies have a follow-up over several decades. We aimed to use these approaches to examine the relationship between cholesterol and prostate cancer. METHODS A cohort of 1997 healthy Norwegian men aged 40-59 years in 1972-75 was followed throughout 2012. Cancer data were extracted from the Cancer Registry of Norway. The association between cholesterol and prostate cancer incidence was assessed using competing risk regression analysis, with adjustment for potential confounders. Date and cause of death was obtained from the Cause of Death Registry of Norway. RESULTS The study cohort had a cancer risk similar to the general Norwegian population. Prostate cancer was registered in 213 men (11 %), including 62 (3 %) with advanced stage at diagnosis. For overall and advanced stage prostate cancer, the incidence was twice as high in the lowest quartile of cholesterol compared to the highest quartile. These associations remained significant after adjustment for age, smoking, physical fitness, BMI, and systolic blood pressure. Furthermore, high physical fitness and low BMI were associated with increased prostate cancer incidence. Sensitivity analyses excluding events during the first 20 years of observation revealed similar results. CONCLUSION Low cholesterol, as well as high physical fitness and low BMI, may be associated with increased risk of prostate cancer. These findings conflict with current prostate cancer prevention recommendations.
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Affiliation(s)
- Trond Heir
- Oslo Ischemia Study, Oslo University Hospital, N-0407, Oslo, Norway.
| | - Ragnhild Sørum Falk
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | | | - Leiv Sandvik
- Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway
| | - Jan Erikssen
- Oslo Ischemia Study, Oslo University Hospital, N-0407, Oslo, Norway
| | - Steinar Tretli
- Department of Research, Cancer Registry of Norway, Oslo, Norway
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Stopsack KH, Gerke TA, Sinnott JA, Penney KL, Tyekucheva S, Sesso HD, Andersson SO, Andrén O, Cerhan JR, Giovannucci EL, Mucci LA, Rider JR. Cholesterol Metabolism and Prostate Cancer Lethality. Cancer Res 2016; 76:4785-90. [PMID: 27325648 PMCID: PMC4987257 DOI: 10.1158/0008-5472.can-16-0903] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 06/05/2016] [Indexed: 12/15/2022]
Abstract
Cholesterol metabolism has been implicated in prostate cancer pathogenesis. Here, we assessed the association of intratumoral mRNA expression of cholesterol synthesis enzymes, transporters, and regulators in tumor specimen at diagnosis and lethal prostate cancer, defined as mortality or metastases from prostate cancer in contrast to nonlethal disease without evidence of metastases after at least 8 years of follow-up. We analyzed the prospective prostate cancer cohorts within the Health Professionals Follow-up Study (n = 249) and the Physicians' Health Study (n = 153) as well as expectantly managed patients in the Swedish Watchful Waiting Study (n = 338). The expression of squalene monooxygenase (SQLE) was associated with lethal cancer in all three cohorts. Men with high SQLE expression (>1 standard deviation above the mean) were 8.3 times (95% confidence interval, 3.5 to 19.7) more likely to have lethal cancer despite therapy compared with men with the mean level of SQLE expression. Absolute SQLE expression was associated with lethal cancer independently from Gleason grade and stage, as was a SQLE expression ratio in tumor versus surrounding benign prostate tissue. Higher SQLE expression was tightly associated with increased histologic markers of angiogenesis. Collectively, this study establishes the prognostic value of intratumoral cholesterol synthesis as measured via SQLE, its second rate-limiting enzyme. SQLE expression at cancer diagnosis is prognostic for lethal prostate cancer both after curative-intent prostatectomy and in a watchful waiting setting, possibly by facilitating micrometastatic disease. Cancer Res; 76(16); 4785-90. ©2016 AACR.
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Affiliation(s)
- Konrad H Stopsack
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
| | - Travis A Gerke
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, College of Medicine and College of Public Health and Health Professions, University of Florida, Gainesville, Florida
| | - Jennifer A Sinnott
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Statistics, Ohio State University, Columbus, Ohio
| | - Kathryn L Penney
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Svitlana Tyekucheva
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Howard D Sesso
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Swen-Olof Andersson
- Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden
| | - Ove Andrén
- Department of Urology, School of Health and Medical Sciences, University of Örebro, Örebro, Sweden
| | - James R Cerhan
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Lorelei A Mucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Jennifer R Rider
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
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Babcook MA, Joshi A, Montellano JA, Shankar E, Gupta S. Statin Use in Prostate Cancer: An Update. Nutr Metab Insights 2016; 9:43-50. [PMID: 27441003 PMCID: PMC4946583 DOI: 10.4137/nmi.s38362] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Revised: 06/22/2016] [Accepted: 06/24/2016] [Indexed: 12/31/2022] Open
Abstract
3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, known as statins, are commonly prescribed for the treatment of hypercholesterolemia and cardiovascular disease. A systematic review was conducted using the keywords “statin and prostate cancer” within the title search engines including PubMed, Web of Science, and the Cochrane Library for relevant research work published between 2004 and December 2015. Although still premature, accumulating clinical evidence suggests that statin use may be beneficial in the prevention and/or treatment of prostate cancer. These human studies consist of meta-analyses of secondary endpoints obtained from randomized, controlled cardiovascular disease clinical trials of statins, patient database, observational studies, and a few, small case–control studies, directly addressing statin use on prostate cancer pathology and recurrence. This review summarizes and discusses the recent clinical literature on statins and prostate cancer with a recommendation to move forward with randomized, placebo-controlled clinical trials, investigating the use of statins. Additional preclinical testing of statins on prostate cancer cell lines and in vivo models is needed to elucidate pathways and determine its efficacy for prevention and/or treatment of prostate cancer, more specifically, the difference in the effectiveness of lipophilic versus hydrophilic statins in prostate cancer.
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Affiliation(s)
- Melissa A Babcook
- Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Aditya Joshi
- Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | | | - Eswar Shankar
- Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Sanjay Gupta
- Department of Urology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH, USA.; The Urology Institute, University Hospitals Case Medical Center, Cleveland, OH, USA.; Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH, USA.; Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Centre, Cleveland, OH, USA
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Sada Y, Hou J, Richardson P, El-Serag H, Davila J. Validation of Case Finding Algorithms for Hepatocellular Cancer From Administrative Data and Electronic Health Records Using Natural Language Processing. Med Care 2016; 54:e9-14. [PMID: 23929403 DOI: 10.1097/mlr.0b013e3182a30373] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Accurate identification of hepatocellular cancer (HCC) cases from automated data is needed for efficient and valid quality improvement initiatives and research. We validated HCC International Classification of Diseases, 9th Revision (ICD-9) codes, and evaluated whether natural language processing by the Automated Retrieval Console (ARC) for document classification improves HCC identification. METHODS We identified a cohort of patients with ICD-9 codes for HCC during 2005-2010 from Veterans Affairs administrative data. Pathology and radiology reports were reviewed to confirm HCC. The positive predictive value (PPV), sensitivity, and specificity of ICD-9 codes were calculated. A split validation study of pathology and radiology reports was performed to develop and validate ARC algorithms. Reports were manually classified as diagnostic of HCC or not. ARC generated document classification algorithms using the Clinical Text Analysis and Knowledge Extraction System. ARC performance was compared with manual classification. PPV, sensitivity, and specificity of ARC were calculated. RESULTS A total of 1138 patients with HCC were identified by ICD-9 codes. On the basis of manual review, 773 had HCC. The HCC ICD-9 code algorithm had a PPV of 0.67, sensitivity of 0.95, and specificity of 0.93. For a random subset of 619 patients, we identified 471 pathology reports for 323 patients and 943 radiology reports for 557 patients. The pathology ARC algorithm had PPV of 0.96, sensitivity of 0.96, and specificity of 0.97. The radiology ARC algorithm had PPV of 0.75, sensitivity of 0.94, and specificity of 0.68. CONCLUSIONS A combined approach of ICD-9 codes and natural language processing of pathology and radiology reports improves HCC case identification in automated data.
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Affiliation(s)
- Yvonne Sada
- *Michael E. DeBakey Veterans Administration Medical Center and Baylor College of Medicine †Health Services Research and Development Section Departments of ‡Oncology §Gastroenterology, Baylor College of Medicine, Houston, TX
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Tan P, Wei S, Tang Z, Gao L, Zhang C, Nie P, Yang L, Wei Q. LDL-lowering therapy and the risk of prostate cancer: a meta-analysis of 6 randomized controlled trials and 36 observational studies. Sci Rep 2016; 6:24521. [PMID: 27075437 PMCID: PMC4830970 DOI: 10.1038/srep24521] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 03/30/2016] [Indexed: 02/08/2023] Open
Abstract
The role of statins in preventing prostate cancer is currently a controversial issue. The aim of this review is to investigate the effects of statins use on prostate cancer risk. Electronic databases (the Cochrane Library, PubMed, Medline, Embase, Web of Science, and ClinicalTrials.gov) were searched systematically up to April, 2015. Weighted averages were reported as relative risk (RR) with 95% confidence intervals (CIs). Statistic heterogeneity scores were assessed with the standard Cochran’s Q test and I2 statistic. The pooled estimates of randomized controlled trials (RCTs) and retrospective studies suggest that statins have a neutral effect on total prostate cancer (RR = 1·02, 95% CI: 0·90–1·14; and RR = 0·91, 95% CI: 0·79–1·02, respectively). This research provides no evidence to suggest that the use of statins for cholesterol lowering is beneficial for the prevention of low-grade or localized prostate cancer, although a plausible association between statins use and the reduction risk of advanced (RR = 0·87, 95% CI: 0·82–0·91) or high-grade prostate cancer (RR = 0·83, 95% CI: 0·66–0·99) is observed. Furthermore, it shows that prostate cancer risk does not statistically significant benefit from long-term statins use.
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Affiliation(s)
- Ping Tan
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shiyou Wei
- Department of Cardiovascular and Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zhuang Tang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Liang Gao
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Chen Zhang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Pan Nie
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Lu Yang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Qiang Wei
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.,Institute of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Low-density lipoprotein receptors play an important role in the inhibition of prostate cancer cell proliferation by statins. Prostate Int 2016; 4:56-60. [PMID: 27358845 PMCID: PMC4916060 DOI: 10.1016/j.prnil.2016.02.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Revised: 02/20/2016] [Accepted: 02/24/2016] [Indexed: 01/06/2023] Open
Abstract
Background There are some reports about the antitumor effects of statins in these days. Statins decrease the level of cholesterol in the blood by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Inhibition of this enzyme decreases intracellular cholesterol synthesis. Thus, the expression of low-density lipoprotein receptor (LDLr) is increased to import more cholesterol from the bloodstream. In this study, we assessed the effects of statins on the proliferation of prostate cancer cells, and studied the relationship between the expression of LDLr and the effects of statins. Methods Simvastatin was used in the experiments. We studied the effect of simvastatin on PC-3 and LNCaP cell proliferation using the MTS assay, and evaluated the expression of LDLr after administration of simvastatin by quantitative polymerase chain reaction and Western blotting. Intracellular cholesterol levels in the prostate cancer cells were measured after administration of simvastatin. Furthermore, small interfering RNA (siRNA) was used to knockdown the gene expression of LDLr. Results In PC-3 cells, simvastatin inhibited cell proliferation. In LNCaP cells, only a high concentration of simvastatin (100μM) inhibited cell proliferation. In LNCaP cells, the protein level of LDLr was increased by simvastatin. In PC-3 cells, the protein levels of LDLr were unregulated. In PC-3 cells, but not in LNCaP cells, intracellular cholesterol levels were significantly decreased by simvastatin. After knocking down LDLr expression by siRNA, intracellular cholesterol levels were decreased, and cell proliferation was inhibited by simvastatin in LNCaP cells. Conclusion Simvastatin inhibited prostate cancer cell growth by decreasing cellular cholesterol and could be more effective in androgen-independent prostate cancer, where there is loss of regulation of LDLr expression. LDLr was shown to play an important role in the statin-induced inhibition of prostate cancer cell proliferation. These results suggest that future studies evaluating the cholesterol-lowering effects of statin may lead to new approaches to the prevention and treatment of prostate cancer.
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45
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Allott EH, Farnan L, Steck SE, Arab L, Su LJ, Mishel M, Fontham ET, Mohler JL, Bensen JT. Statin Use and Prostate Cancer Aggressiveness: Results from the Population-Based North Carolina–Louisiana Prostate Cancer Project. Cancer Epidemiol Biomarkers Prev 2016; 25:670-7. [DOI: 10.1158/1055-9965.epi-15-0631] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 10/24/2015] [Indexed: 11/16/2022] Open
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Allott EH, Howard LE, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Freedland SJ. Racial Differences in the Association Between Preoperative Serum Cholesterol and Prostate Cancer Recurrence: Results from the SEARCH Database. Cancer Epidemiol Biomarkers Prev 2016; 25:547-54. [PMID: 26809276 DOI: 10.1158/1055-9965.epi-15-0876] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 01/08/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Black men are disproportionately affected by both cardiovascular disease and prostate cancer. Epidemiologic evidence linking dyslipidemia, an established cardiovascular risk factor, and prostate cancer progression is mixed. As existing studies were conducted in predominantly non-black populations, research on black men is lacking. METHODS We identified 628 black and 1,020 non-black men who underwent radical prostatectomy and never used statins before surgery in the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Median follow-up was 2.9 years. The impact of preoperative hypercholesterolemia on risk of biochemical recurrence was examined using multivariable, race-stratified proportional hazards. In secondary analysis, we examined associations with low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides, overall and among men with dyslipidemia. RESULTS High cholesterol was associated with increased risk of recurrence in black [HR(per10 mg/dL) 1.06; 95% confidence interval (CI), 1.02-1.11] but not non-black men (HR(per10 mg/dL) 0.99; 95% CI, 0.95-1.03; P(interaction) = 0.011). Elevated triglycerides were associated with increased risk in both black and non-black men (HR(per10 mg/dL) 1.02; 95% CI, 1.00-1.03 and 1.02; 95% CI, 1.00-1.02, respectively; P(interaction) = 0.458). There were no significant associations between LDL or HDL and recurrence risk in either race. Associations with cholesterol, LDL, and triglycerides were similar among men with dyslipidemia, but low HDL was associated with increased risk of recurrence in black, but not non-black men with dyslipidemia (P(interaction) = 0.047). CONCLUSION Elevated cholesterol was a risk factor for recurrence in black but not non-black men, whereas high triglycerides were associated with increased risk regardless of race. IMPACT Significantly contrasting associations by race may provide insight into prostate cancer racial disparities.
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Affiliation(s)
- Emma H Allott
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Lauren E Howard
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - William J Aronson
- Urology Section, Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California. Department of Urology, UCLA School of Medicine, Los Angeles, California
| | - Martha K Terris
- Section of Urology, Veterans Affairs Medical Center, Augusta, Georgia. Section of Urology, Medical College of Georgia, Augusta, Georgia
| | - Christopher J Kane
- Urology Department, University of California San Diego Health System, San Diego, California
| | | | - Matthew R Cooperberg
- Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California
| | - Stephen J Freedland
- Cedars Sinai Medical Center, Los Angeles, California. Division of Urology, Veterans Affairs Medical Center, Durham, North Carolina.
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47
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Bayne CE, Jarrett TW. Cancer of the Prostate: Incidence in the USA. Prostate Cancer 2016. [DOI: 10.1016/b978-0-12-800077-9.00014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Allott EH, Hursting SD. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr Relat Cancer 2015; 22:R365-86. [PMID: 26373570 PMCID: PMC4631382 DOI: 10.1530/erc-15-0400] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/15/2015] [Indexed: 12/11/2022]
Abstract
Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link.
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Affiliation(s)
- Emma H Allott
- Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA
| | - Stephen D Hursting
- Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA
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Jung J, Lee C, Lee C, Kwon T, You D, Jeong IG, Hong JH, Ahn H, Kim CS. Effects of statin use on the response duration to androgen deprivation therapy in metastatic prostate cancer. Korean J Urol 2015; 56:630-6. [PMID: 26366275 PMCID: PMC4565897 DOI: 10.4111/kju.2015.56.9.630] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Accepted: 07/02/2015] [Indexed: 11/21/2022] Open
Abstract
Purpose To determine whether statin use delays the development of castration-resistant prostate cancer (CRPC) in patients with metastatic prostate cancer treated with androgen deprivation therapy (ADT). Materials and Methods A total of 171 patients with metastatic prostate cancer at the time of diagnosis who were treated with ADT between January 1997 and December 2013 were retrospectively analyzed. The patients were classified into two groups: the nonstatin use group (A group) and the statin use group (B group). Multivariate analysis was performed on statin use and other factors considered likely to have an effect on the time to progression to CRPC. Results The mean patient age was 67.1±9.1 years, and the mean follow-up period was 52 months. The mean initial prostate-specific antigen (PSA) level was 537 ng/mL. Of the 171 patients, 125 (73%) were in group A and 46 (27%) were in group B. The time to progression to CRPC was 22.7 months in group A and 30.5 months in group B, and this difference was significant (p=0.032). Blood cholesterol and initial PSA levels did not differ significantly according to the time to progression to CRPC (p=0.288, p=0.198). Multivariate analysis using the Cox regression method showed that not having diabetes (p=0.037) and using a statin (p=0.045) significantly increased the odds ratio of a longer progression to CRPC. Conclusions Statin use in metastatic prostate cancer patients appears to delay the progression to CRPC. Large-scale, long-term follow-up studies are needed to validate this finding.
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Affiliation(s)
- Jaeyoon Jung
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chunwoo Lee
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chanwoo Lee
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Taekmin Kwon
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dalsan You
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - In Gab Jeong
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun Hyuk Hong
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hanjong Ahn
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Choung-Soo Kim
- Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Gordon JA, Midha A, Szeitz A, Ghaffari M, Adomat HH, Guo Y, Klassen TL, Guns ES, Wasan KM, Cox ME. Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts. Prostate Cancer Prostatic Dis 2015; 19:21-7. [DOI: 10.1038/pcan.2015.37] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2015] [Revised: 06/24/2015] [Accepted: 06/26/2015] [Indexed: 12/11/2022]
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