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1
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Wang T, Yao Y, Gao X, Luan H, Wang X, Liu L, Sun C. Genetic association of lipids and lipid-lowering drug target genes with breast cancer. Discov Oncol 2025; 16:331. [PMID: 40095250 PMCID: PMC11914663 DOI: 10.1007/s12672-025-02041-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 03/03/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Although several preclinical and epidemiological studies have shown that blood lipids and lipid-lowering drugs can reduce the risk of breast cancer, this finding remains controversial. This study aimed to explore the causal relationship between dyslipidemia,lipid-lowering drugs, and breast cancer. We also aimed to evaluate the potential impact of lipid-lowering drug targets on breast cancer. METHOD Data of 431 lipid- and lipid-related phenotypes were obtained from genome-wide association study (GWAS), and mendelian randomization (MR) analyses were performed using two independent breast cancer datasets as endpoints. Genetic variants associated with genes encoding lipid-lowering drug targets were extracted from the Global Lipid Genetics Consortium. Expression quantitative trait loci data in relevant tissues were used to further validate lipid-lowering drug targets that reached significance and combined with bioinformatics approaches for molecular expression and prognostic exploration. Further mediation analyses were performed to explore potential mediators. RESULT In two independent datasets, phosphatidylcholine (18:1_0:0 levels) was associated with breast cancer risk (discovery: odds ratio (OR) = 1.255 [95% confidence interval (CI) 1.120-1.406]; p = 8.936 × 10-5, replication: OR = 1.016 [95% CI, 1.003-1.030]; p = 0.017), HMG- CoA reductase (HMGCR) inhibition was genetically modeled and associated with a reduced risk of breast cancer (discovery: OR = 0.833 [95% CI 0.752-0.923], p = 5.12 × 10-4; replication: OR = 0.975 [95% CI 0.960-0.990], p = 1.65 × 10-3). There was a significant MR correlation between HMGCR expression in whole blood and breast cancer (OR = 1.11 [95% 1.01-1.22] p = 0.04). Bioinformatics analysis revealed that HMGCR expression higher in breast cancer tissues than in normal tissues, along with poor overall survival and relapse-free survival, and was associated with multiple immune cell infiltration. Finally, the mediation analysis showed that HMGCR inhibitors affected breast cancer through different immune cell phenotypes and C-reactive protein levels. CONCLUSION In this study, we found for the first time that phosphatidylcholine (18:1_0:0) levels are associated with breast cancer risk. We found that HMGCR inhibitors are associated with a reduced risk of breast cancer, and part of their action may be through pathways other than lipid-lowering, including modulation of immune function and reduction of inflammation represented by C-reactive protein levels.
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Affiliation(s)
- Tianhua Wang
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yan Yao
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China
| | - Xinhai Gao
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hao Luan
- Innovation Research Institute of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xue Wang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
| | - Lijuan Liu
- College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China.
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.
| | - Changgang Sun
- Department of Oncology, Weifang Traditional Chinese Hospital, Weifang, China.
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China.
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Kato C, Iizuka-Ohashi M, Honda M, Konishi E, Yokota I, Boku S, Mizuta N, Morita M, Sakaguchi K, Taguchi T, Watanabe M, Naoi Y. Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167458. [PMID: 39128642 DOI: 10.1016/j.bbadis.2024.167458] [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: 01/27/2024] [Revised: 07/26/2024] [Accepted: 08/07/2024] [Indexed: 08/13/2024]
Abstract
The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.
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Affiliation(s)
- Chikage Kato
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mahiro Iizuka-Ohashi
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Mizuki Honda
- Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Eiichi Konishi
- Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Isao Yokota
- Department of Biostatistics, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Shogen Boku
- Cancer Treatment Center, Kansai Medical University Hospital, Osaka, Japan
| | | | - Midori Morita
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Koichi Sakaguchi
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tetsuya Taguchi
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Motoki Watanabe
- Department of Molecular-Targeting Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan.
| | - Yasuto Naoi
- Department of Endocrine and Breast Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Hillis AL, Martin TD, Manchester HE, Högström J, Zhang N, Lecky E, Kozlova N, Lee J, Persky NS, Root DE, Brown M, Cichowski K, Elledge SJ, Muranen T, Fruman DA, Barry ST, Clohessy JG, Madsen RR, Toker A. Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer. Cancer Res 2024; 84:3250-3266. [PMID: 39024548 PMCID: PMC11443248 DOI: 10.1158/0008-5472.can-24-0970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/22/2024] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.
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Affiliation(s)
- Alissandra L. Hillis
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - Timothy D. Martin
- Division of Genetics, Department of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts.
| | - Haley E. Manchester
- Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Jenny Högström
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - Na Zhang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
| | - Emmalyn Lecky
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - Nina Kozlova
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - Jonah Lee
- Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | | | - David E. Root
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
| | - Karen Cichowski
- Genetics Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Stephen J. Elledge
- Division of Genetics, Department of Genetics, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts.
| | - Taru Muranen
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
| | - David A. Fruman
- Department of Molecular Biology and Biochemistry, University of California, Irvine, California.
| | - Simon T. Barry
- Bioscience, Discovery, Oncology Research and Development, AstraZeneca, Cambridge, Massachusetts.
| | - John G. Clohessy
- Preclinical Murine Pharmacogenetics Facility and Mouse Hospital, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Ralitsa R. Madsen
- MRC-Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
| | - Alex Toker
- Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
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Filaferro L, Zaccarelli F, Niccolini GF, Colizza A, Zoccali F, Grasso M, Fusconi M. Are statins onco- suppressive agents for every type of tumor? A systematic review of literature. Expert Rev Anticancer Ther 2024; 24:435-445. [PMID: 38609343 DOI: 10.1080/14737140.2024.2343338] [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: 05/22/2023] [Accepted: 04/11/2024] [Indexed: 04/14/2024]
Abstract
INTRODUCTION Statins, in the role of anti-cancer agents, have been used in many types of cancers with results in some cases promising while, in others, disappointing. AREAS COVERED The purpose of this review is to identify and highlight data from literature on the successes or failure of using statins as anti-cancer agents. We asked ourselves the following two questions:1. Could statins, which are taken mostly to reduce cardiovascular risk, guarantee a lower incidence or a better cancer disease prognosis, concerning local recurrence, metastasis or mortality?2. Does statins intake (before and/or after cancer diagnosis) improve the prognosis or increase the chemotherapeutic action when combined with other anticancer therapies? For the first question twenty-seven manuscripts have been selected, for the second one, twenty-eight. EXPERT OPINION There are data which correlate statins with a possible tumor suppressive action among the following cancers: breast, lung, prostate and head and neck. Lastly, for gastric cancer and colorectal there is no evidence of a correlation. The onco-suppressive efficacy of statins is mainly related to the histopathological and/or molecular characteristics of the tumor cells, which have different characteristics.
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Affiliation(s)
- Luca Filaferro
- Department of Sense Organs, Sapienza University, Rome, Italy
| | | | | | - Andrea Colizza
- Department of Sense Organs, Sapienza University, Rome, Italy
| | | | | | - Massimo Fusconi
- Department of Sense Organs, Sapienza University, Rome, Italy
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5
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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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6
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Tripathi S, Gupta E, Galande S. Statins as anti-tumor agents: A paradigm for repurposed drugs. Cancer Rep (Hoboken) 2024; 7:e2078. [PMID: 38711272 PMCID: PMC11074523 DOI: 10.1002/cnr2.2078] [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: 11/14/2023] [Revised: 03/28/2024] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Statins, frequently prescribed medications, work by inhibiting the rate-limiting enzyme HMG-CoA reductase (HMGCR) in the mevalonate pathway to reduce cholesterol levels. Due to their multifaceted benefits, statins are being adapted for use as cost-efficient, safe and effective anti-cancer treatments. Several studies have shown that specific types of cancer are responsive to statin medications since they rely on the mevalonate pathway for their growth and survival. RECENT FINDINGS Statin are a class of drugs known for their potent inhibition of cholesterol production and are typically prescribed to treat high cholesterol levels. Nevertheless, there is growing interest in repurposing statins for the treatment of malignant neoplastic diseases, often in conjunction with chemotherapy and radiotherapy. The mechanism behind statin treatment includes targeting apoptosis through the BCL2 signaling pathway, regulating the cell cycle via the p53-YAP axis, and imparting epigenetic modulations by altering methylation patterns on CpG islands and histone acetylation by downregulating DNMTs and HDACs respectively. Notably, some studies have suggested a potential chemo-preventive effect, as decreased occurrence of tumor relapse and enhanced survival rate were reported in patients undergoing long-term statin therapy. However, the definitive endorsement of statin usage in cancer therapy hinges on population based clinical studies with larger patient cohorts and extended follow-up periods. CONCLUSIONS The potential of anti-cancer properties of statins seems to reach beyond their influence on cholesterol production. Further investigations are necessary to uncover their effects on cancer promoting signaling pathways. Given their distinct attributes, statins might emerge as promising contenders in the fight against tumorigenesis, as they appear to enhance the efficacy and address the limitations of conventional cancer treatments.
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Affiliation(s)
- Sneha Tripathi
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Ekta Gupta
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Sanjeev Galande
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
- Centre of Excellence in Epigenetics, Department of Life SciencesShiv Nadar Institution of EminenceGautam Buddha NagarIndia
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7
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Mahmud I, Tian G, Wang J, Hutchinson TE, Kim BJ, Awasthee N, Hale S, Meng C, Moore A, Zhao L, Lewis JE, Waddell A, Wu S, Steger JM, Lydon ML, Chait A, Zhao LY, Ding H, Li JL, Purayil HT, Huo Z, Daaka Y, Garrett TJ, Liao D. DAXX drives de novo lipogenesis and contributes to tumorigenesis. Nat Commun 2023; 14:1927. [PMID: 37045819 PMCID: PMC10097704 DOI: 10.1038/s41467-023-37501-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Cancer cells exhibit elevated lipid synthesis. In breast and other cancer types, genes involved in lipid production are highly upregulated, but the mechanisms that control their expression remain poorly understood. Using integrated transcriptomic, lipidomic, and molecular studies, here we report that DAXX is a regulator of oncogenic lipogenesis. DAXX depletion attenuates, while its overexpression enhances, lipogenic gene expression, lipogenesis, and tumor growth. Mechanistically, DAXX interacts with SREBP1 and SREBP2 and activates SREBP-mediated transcription. DAXX associates with lipogenic gene promoters through SREBPs. Underscoring the critical roles for the DAXX-SREBP interaction for lipogenesis, SREBP2 knockdown attenuates tumor growth in cells with DAXX overexpression, and DAXX mutants unable to bind SREBP1/2 have weakened activity in promoting lipogenesis and tumor growth. Remarkably, a DAXX mutant deficient of SUMO-binding fails to activate SREBP1/2 and lipogenesis due to impaired SREBP binding and chromatin recruitment and is defective of stimulating tumorigenesis. Hence, DAXX's SUMO-binding activity is critical to oncogenic lipogenesis. Notably, a peptide corresponding to DAXX's C-terminal SUMO-interacting motif (SIM2) is cell-membrane permeable, disrupts the DAXX-SREBP1/2 interactions, and inhibits lipogenesis and tumor growth. These results establish DAXX as a regulator of lipogenesis and a potential therapeutic target for cancer therapy.
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Affiliation(s)
- Iqbal Mahmud
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
- Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guimei Tian
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Jia Wang
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
- The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, 450008, Zhengzhou, Henan, China
| | - Tarun E Hutchinson
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Brandon J Kim
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Nikee Awasthee
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Seth Hale
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Chengcheng Meng
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Allison Moore
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Liming Zhao
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Jessica E Lewis
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Aaron Waddell
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Shangtao Wu
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Julia M Steger
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - McKenzie L Lydon
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Aaron Chait
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Lisa Y Zhao
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
- Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Haocheng Ding
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Jian-Liang Li
- Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
| | - Hamsa Thayele Purayil
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Zhiguang Huo
- Department of Biostatistics, University of Florida, Gainesville, FL, USA
| | - Yehia Daaka
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA
| | - Timothy J Garrett
- Southeast Center for Integrated Metabolomics, Clinical and Translational Science Institute, University of Florida, Gainesville, FL, USA
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Daiqing Liao
- Department of Anatomy and Cell Biology, UF Health Cancer Center, University of Florida College of Medicine, Gainesville, FL, USA.
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8
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Yulian ED, Siregar NC, Sudijono B, Hwei LRY. The role of HMGCR expression in combination therapy of simvastatin and FAC treated locally advanced breast cancer patients. Breast Dis 2023; 42:73-83. [PMID: 36938720 DOI: 10.3233/bd-220021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
OBJECTIVE Several studies have shown the role of statin added to the patient's chemotherapy regimen and the role of Hydroxymethylglutaryl-CoA Reductase (HMGCR) expression in predicting breast cancer patient outcomes. In our previous study, adding statins improved clinical and pathological responses in LABC patients. Furthermore, we planned to study statin's role as a combination to neoadjuvant chemotherapy (NAC) in treating locally advanced breast cancers on the basis of HMGCR expression. Moreover, we aimed to study the association between the patients' clinicopathological characteristics and HMGCR expression. METHODS This study is a randomized, double-blinded, placebo-controlled trial in two health centers in Indonesia. Each patient enrolled with written informed consent and then randomized to receive either simvastatin 40 mg/day or a placebo, combined with the fluorouracil, adriamycin, and cyclophosphamide (FAC) NAC. RESULTS HMGCR was associated with low staging and normal serum cholesterol in the high Ki67 level group (p = 0.042 and p = 0.021, respectively). The pre-and post-chemotherapy tumor sizes are significantly correlated in two groups (HMGCR negative expression, p = 0.000 and HMGCR moderate expression, p = 0.001) with a more considerable average decrease in tumor size compared to HMGCR strong expression group. CONCLUSION Statin therapy might work better in HMGCR-negative or low-expression tumors, although HGMCR expression is associated with better clinical parameters in our study.
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Affiliation(s)
- Erwin Danil Yulian
- Division of Surgical Oncology, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Nurjati Chairani Siregar
- Department of Pathology, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | | | - Lie Rebecca Yen Hwei
- Division of Surgical Oncology, Department of Surgery, Dr. Cipto Mangunkusumo General Hospital, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
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van Leeuwen JE, Ba-Alawi W, Branchard E, Cruickshank J, Schormann W, Longo J, Silvester J, Gross PL, Andrews DW, Cescon DW, Haibe-Kains B, Penn LZ, Gendoo DMA. Computational pharmacogenomic screen identifies drugs that potentiate the anti-breast cancer activity of statins. Nat Commun 2022; 13:6323. [PMID: 36280687 PMCID: PMC9592602 DOI: 10.1038/s41467-022-33144-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 09/02/2022] [Indexed: 12/25/2022] Open
Abstract
Statins, a family of FDA-approved cholesterol-lowering drugs that inhibit the rate-limiting enzyme of the mevalonate metabolic pathway, have demonstrated anticancer activity. Evidence shows that dipyridamole potentiates statin-induced cancer cell death by blocking a restorative feedback loop triggered by statin treatment. Leveraging this knowledge, we develop an integrative pharmacogenomics pipeline to identify compounds similar to dipyridamole at the level of drug structure, cell sensitivity and molecular perturbation. To overcome the complex polypharmacology of dipyridamole, we focus our pharmacogenomics pipeline on mevalonate pathway genes, which we name mevalonate drug-network fusion (MVA-DNF). We validate top-ranked compounds, nelfinavir and honokiol, and identify that low expression of the canonical epithelial cell marker, E-cadherin, is associated with statin-compound synergy. Analysis of remaining prioritized hits led to the validation of additional compounds, clotrimazole and vemurafenib. Thus, our computational pharmacogenomic approach identifies actionable compounds with pathway-specific activities.
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Affiliation(s)
- Jenna E. van Leeuwen
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Wail Ba-Alawi
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Emily Branchard
- grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Jennifer Cruickshank
- grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Wiebke Schormann
- grid.17063.330000 0001 2157 2938Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5 Canada
| | - Joseph Longo
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Jennifer Silvester
- grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Peter L. Gross
- grid.25073.330000 0004 1936 8227Department of Medicine, McMaster University, 1280 Main St W, Hamilton, ON L8S 4L8 Canada
| | - David W. Andrews
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.17063.330000 0001 2157 2938Biological Sciences, Sunnybrook Research Institute, University of Toronto, Toronto, ON M4N 3M5 Canada
| | - David W. Cescon
- grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.17063.330000 0001 2157 2938Division of Medical Oncology and Hematology, Department of Medicine, University of Toronto, 27 King’s College Circle, Toronto, ON M5S 1A1 Canada
| | - Benjamin Haibe-Kains
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.17063.330000 0001 2157 2938Department of Computer Science, University of Toronto, 10 King’s College Road, Toronto, ON M5S 3G4 Canada ,grid.419890.d0000 0004 0626 690XOntario Institute of Cancer Research, 661 University Avenue, Suite 510, Toronto, ON M5G 0A3 Canada
| | - Linda Z. Penn
- grid.17063.330000 0001 2157 2938Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON M5G 1L7 Canada ,grid.231844.80000 0004 0474 0428Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON M5G 1L7 Canada
| | - Deena M. A. Gendoo
- grid.6572.60000 0004 1936 7486Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, Birmingham, B15 2TT UK ,grid.6572.60000 0004 1936 7486Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, Birmingham, B15 2TT UK
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10
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Classification and Prognostic Characteristics of Hepatocellular Carcinoma Based on Glycolysis Cholesterol Synthesis Axis. JOURNAL OF ONCOLOGY 2022; 2022:2014625. [PMID: 36213830 PMCID: PMC9546679 DOI: 10.1155/2022/2014625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 07/04/2022] [Accepted: 07/12/2022] [Indexed: 01/27/2023]
Abstract
Background Liver hepatocellular carcinoma (LIHC) is among the most frequent causes of cancer-related death across the world with a considerably poor prognosis. The current study targeted providing a new type of LIHC from the perspective of the glycolysis/cholesterol synthesis axis, predicting its prognostic characteristics, and exploring the potential role and mechanism of the glycolysis/cholesterol synthesis axis in the occurrence and development of LIHC. Methods Based on the two expression profile data and clinical information of LIHC in The Cancer Genome Atlas (TCGA) database and hepatocellular carcinoma database (HCCDB), as well as glycolysis/cholesterol-related genes from the Molecular Signatures Database (MSigDB), unsupervised consistent clustering method was used to identify molecular subtypes. In addition, the differential genes were identified by limma package, and then the gene set was enriched, analyzed, and annotated by WebGestaltR package. At the same time, the immune infiltration analysis of tumor samples was carried out using the ESTIMATE to evaluate the tumor immune score of the samples. Finally, the differences in clinical characteristics among molecular subtypes were measured using univariate and multivariate Cox analyses. Results According to the median standardized expression levels of glycolysis/cholesterol production genes, samples were divided into four groups (molecular subtypes): Quiescent group, Glycolysis group, Cholesterol group, and Mixed group. Significant prognostic differences were observed among the four groups. In both TCGA and HCCDB18 datasets, the prognosis of subtype Mixed was the worst, while Quiescent had a good prognosis. Cell cycle and oncogenic pathways were significantly enriched in the Mixed group. In addition, glycolysis and cholesterol production gene expressions were related to the prognostic LIHC subtype classification genes' expression levels. Conclusion Metabolic classification regarding glycolysis and cholesterol production pathways provided new insights into the biological aspects of LIHC molecular subtypes and might help to develop personalized therapies for unique tumor metabolic profiles.
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11
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The mevalonate pathway in breast cancer biology. Cancer Lett 2022; 542:215761. [DOI: 10.1016/j.canlet.2022.215761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/25/2022] [Accepted: 05/26/2022] [Indexed: 02/07/2023]
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12
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Statins and prostate cancer-hype or hope? The biological perspective. Prostate Cancer Prostatic Dis 2022; 25:650-656. [PMID: 35768578 DOI: 10.1038/s41391-022-00557-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/14/2022] [Accepted: 05/27/2022] [Indexed: 01/14/2023]
Abstract
Growing evidence suggests that men prescribed a statin for cholesterol control have a lower risk of advanced prostate cancer (PCa) and improved treatment outcomes; however, the mechanism by which statins elicit their anti-neoplastic effects is not well understood and is likely multifaceted. Statins are potent and specific inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), the rate-limiting enzyme of the mevalonate (MVA) metabolic pathway. This two-part series is a review of the observational and experimental data on statins as anti-cancer agents in PCa. In this article, we describe the functional role that deregulated MVA metabolism plays in PCa progression and summarize the biological evidence and rationale for targeting the MVA pathway, with statins and other agents, for the treatment of PCa.
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13
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Jung M, Lee K, Im Y, Seok SH, Chung H, Kim DY, Han D, Lee CH, Hwang EH, Park SY, Koh J, Kim B, Nikas IP, Lee H, Hwang D, Ryu HS. Nicotinamide (niacin) supplement increases lipid metabolism and ROS‐induced energy disruption in triple‐negative breast cancer: potential for drug repositioning as an anti‐tumor agent. Mol Oncol 2022; 16:1795-1815. [PMID: 35278276 PMCID: PMC9067146 DOI: 10.1002/1878-0261.13209] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/27/2022] [Accepted: 03/10/2022] [Indexed: 11/08/2022] Open
Abstract
Metabolic dysregulation is an important hallmark of cancer. Nicotinamide (NAM), a water‐soluble amide form of niacin (vitamin B3), is currently available as a supplement for maintaining general physiologic functions. NAM is a crucial regulator of mitochondrial metabolism and redox reactions. In this study, we aimed to identify the mechanistic link between NAM‐induced metabolic regulation and the therapeutic efficacy of NAM in triple‐negative breast cancer (TNBC). The combined analysis using multiomics systems biology showed that NAM decreased mitochondrial membrane potential and ATP production, but increased the activities of reverse electron transport (RET), fatty acid β‐oxidation and glycerophospholipid/sphingolipid metabolic pathways in TNBC, collectively leading to an increase in the levels of reactive oxygen species (ROS). The increased ROS levels triggered apoptosis and suppressed tumour growth and metastasis of TNBC in both human organoids and xenograft mouse models. Our results showed that NAM treatment leads to cancer cell death in TNBC via mitochondrial dysfunction and activation of ROS by bifurcating metabolic pathways (RET and lipid metabolism); this provides insights into the repositioning of NAM supplement as a next‐generation anti‐metabolic agent for TNBC treatment.
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Affiliation(s)
- Minsun Jung
- Department of Pathology Seoul National University College of Medicine Seoul Republic of Korea
- Department of Pathology Severance Hospital Yonsei University College of Medicine Seoul Republic of Korea
| | - Kyung‐Min Lee
- Center for Medical Innovation Biomedical Research Institute Seoul National University Hospital Seoul Republic of Korea
| | - Yebin Im
- School of Biological Sciences Seoul National University Seoul Republic of Korea
| | - Seung Hyeok Seok
- Department of Microbiology and Immunology and Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea
| | - Hyewon Chung
- Department of Microbiology and Immunology and Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea
| | - Da Young Kim
- Department of Microbiology and Immunology and Department of Biomedical Sciences Seoul National University College of Medicine Seoul Republic of Korea
| | - Dohyun Han
- Proteomics Core Facility Biomedical Research Institute Seoul National University Hospital Seoul Republic of Korea
| | - Cheng Hyun Lee
- Department of Pathology Seoul National University College of Medicine Seoul Republic of Korea
| | - Eun Hye Hwang
- Department of Pathology Seoul National University College of Medicine Seoul Republic of Korea
| | - Soo Young Park
- Department of Pathology Seoul National University College of Medicine Seoul Republic of Korea
- Center for Medical Innovation Biomedical Research Institute Seoul National University Hospital Seoul Republic of Korea
- Department of Pathology Seoul National University Hospital Seoul Republic of Korea
| | - Jiwon Koh
- Department of Pathology Seoul National University Hospital Seoul Republic of Korea
| | - Bohyun Kim
- Department of Pathology Seoul National University Hospital Seoul Republic of Korea
| | - Ilias P Nikas
- School of Medicine European University Cyprus 2404 Nicosia Cyprus
| | - Hyebin Lee
- Department of Radiation Oncology Kangbuk Samsung Hospital Sungkyunkwan University School of Medicine Seoul Republic of Korea
| | - Daehee Hwang
- School of Biological Sciences Seoul National University Seoul Republic of Korea
| | - Han Suk Ryu
- Department of Pathology Seoul National University College of Medicine Seoul Republic of Korea
- Center for Medical Innovation Biomedical Research Institute Seoul National University Hospital Seoul Republic of Korea
- Department of Pathology Seoul National University Hospital Seoul Republic of Korea
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14
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Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer. Pharmaceuticals (Basel) 2022; 15:ph15020151. [PMID: 35215263 PMCID: PMC8877351 DOI: 10.3390/ph15020151] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 12/15/2022] Open
Abstract
The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering’.
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15
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Uemura N, Hayashi H, Baba H. Statin as a therapeutic agent in gastroenterological cancer. World J Gastrointest Oncol 2022; 14:110-123. [PMID: 35116106 PMCID: PMC8790423 DOI: 10.4251/wjgo.v14.i1.110] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/19/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Statins inhibit 3-hydroxy-3-methylglutaryl-CoA reductase, the rate-limiting enzyme of the mevalonate pathway, and are widely used as an effective and safe approach handle hypercholesterolemia. The mevalonate pathway is a vital metabolic pathway that uses acetyl-CoA to generate isoprenoids and sterols that are crucial to tumor growth and progression. Multiple studies have indicated that statins improve patient prognosis in various carcinomas. Basic research on the mechanisms underlying the antitumor effects of statins is underway. The development of new anti-cancer drugs is progressing, but increasing medical costs from drug development have become a major obstacle. Readily available, inexpensive and well-tolerated drugs like statins have not yet been successfully repurposed for cancer treatment. Identifying the cancer patients that may benefit from statins is key to improved patient treatment. This review summarizes recent advances in statin research in cancer and suggests important considerations for the clinical use of statins to improve outcomes for cancer patients.
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Affiliation(s)
- Norio Uemura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromitsu Hayashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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16
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Inasu M, Feldt M, Jernström H, Borgquist S, Harborg S. Statin use and patterns of breast cancer recurrence in the Malmö Diet and Cancer Study. Breast 2022; 61:123-128. [PMID: 34995921 PMCID: PMC8741597 DOI: 10.1016/j.breast.2022.01.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/28/2021] [Accepted: 01/03/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear. PATIENTS AND METHODS We identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users. RESULTS The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 [95% CI: 0.82-0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 [95% CI: 0.80-0.94]) but not loco-regional recurrence (HRadj = 0.97 [95% CI: 0.87-1.08]). CONCLUSION In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.
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Affiliation(s)
- Maria Inasu
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
| | - Maria Feldt
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Helena Jernström
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Signe Borgquist
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden; Department of Oncology, Aarhus University/Aarhus University Hospital, Denmark
| | - Sixten Harborg
- Department of Oncology, Aarhus University/Aarhus University Hospital, Denmark.
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17
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Coradini D. De novo cholesterol biosynthesis: an additional therapeutic target for the treatment of postmenopausal breast cancer with excessive adipose tissue. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2022; 3:841-852. [PMID: 36654818 PMCID: PMC9834634 DOI: 10.37349/etat.2022.00116] [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: 08/23/2022] [Accepted: 11/08/2022] [Indexed: 12/29/2022] Open
Abstract
The onset and development of breast cancer in postmenopausal women are associated with closely related individual-dependent factors, including weight gain and high levels of circulating androgens. Adipose tissue is the most peripheral site of aromatase enzyme synthesis; therefore, the excessive accumulation of visceral fat results in increased androgens aromatization and estradiol production that provides the microenvironment favorable to tumorigenesis in mammary epithelial cells expressing estrogen receptors (ERs). Moreover, to meet the increased requirement of cholesterol for cell membrane assembly and the production of steroid hormones to sustain their proliferation, ER-positive cells activate de novo cholesterol biosynthesis and subsequent steroidogenesis. Several approaches have been followed to neutralize the de novo cholesterol synthesis, including specific enzyme inhibitors, statins, and, more recently, metformin. Cumulating evidence indicated that inhibiting cholesterol biosynthesis by statins and metformin may be a promising therapeutic strategy to block breast cancer progression. Unlike antiestrogens and aromatase inhibitors (AIs) which compete for binding to ER and inhibit androgens aromatization, respectively, statins block the production of mevalonic acid by inhibiting the activity of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and metformin hampers the activation of the sterol regulatory element-binding protein 2 (SREBP2) transcription factor, thus inhibiting the synthesis of several enzymes involved in cholesterol biosynthesis. Noteworthy, statins and metformin not only improve the prognosis of overweight patients with ER-positive cancer but also improve the prognosis of patients with triple-negative breast cancer, the aggressive tumor subtype that lacks, at present, specific therapy.
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Affiliation(s)
- Danila Coradini
- Department of Clinical Sciences and Community Health, Campus Cascina Rosa, University of Milan, 20133 Milan, Italy,Correspondence: Danila Coradini, Department of Clinical Sciences and Community Health, Campus Cascina Rosa, University of Milan, Via Vanzetti 5, 20133 Milan, Italy.
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18
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Ishikawa T, Osaki T, Sugiura A, Tashiro J, Warita T, Hosaka YZ, Warita K. Atorvastatin preferentially inhibits the growth of high ZEB-expressing canine cancer cells. Vet Comp Oncol 2021; 20:313-323. [PMID: 34657361 DOI: 10.1111/vco.12778] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 10/03/2021] [Accepted: 10/13/2021] [Indexed: 11/30/2022]
Abstract
The epithelial-to-mesenchymal transition (EMT) is fundamental in cancer progression and contributes to the acquisition of malignant properties. The statin class of cholesterol-lowering drugs exhibits pleiotropic anticancer effects in vitro and in vivo, and many epidemiologic studies have reported a correlation between statin use and reduced cancer mortality. We have shown previously that sensitivity to the anti-proliferative effect of statins varies among human cancer cells and statins are more effective against mesenchymal-like cells than epithelial-like ones in human cancers. There have only been few reports on the application of statins to cancer therapy in veterinary medicine, and differences in statin sensitivity among canine cancer cells have not been examined. In this study, we aimed to clarify the correlation between sensitivity to atorvastatin and epithelial/mesenchymal states in 11 canine cancer cell lines derived from mammary gland, squamous cell carcinoma, lung, and melanoma. Sensitivity to atorvastatin varied among canine cancer cells, with IC50 values ranging from 5.92 to 71.5 μM at 48 h, which were higher than the plasma concentrations clinically achieved with statin therapy. Atorvastatin preferentially attenuated the proliferation of mesenchymal-like cells. In particular, highly statin-sensitive cells were characterized by aberrant expression of the ZEB family of EMT-inducing transcription factors. However, ZEB2 silencing in highly sensitive cells did not induce resistance to atorvastatin. Taken together, these results suggest that high expression of ZEB is a characteristic of highly statin-sensitive cells and could be a molecular marker for predicting whether cancers are sensitive to statins, though ZEB itself does not confer statin sensitivity.
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Affiliation(s)
- Takuro Ishikawa
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomohiro Osaki
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Clinical Medicine, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Akihiro Sugiura
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Jiro Tashiro
- Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Tomoko Warita
- Department of Biomedical Sciences, School of Biological and Environmental Science, Kwansei Gakuin University, Hyogo, Japan
| | - Yoshinao Z Hosaka
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
| | - Katsuhiko Warita
- Laboratory of Basic Veterinary Science, United Graduate School of Veterinary Science, Yamaguchi University, Yamaguchi, Japan.,Department of Veterinary Anatomy, School of Veterinary Medicine, Tottori University, Tottori, Japan
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19
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Zhong PC, Shu R, Wu HW, Liu ZW, Shen XL, Hu YJ. Altered gene expression in glycolysis-cholesterol synthesis axis correlates with outcome of triple-negative breast cancer. Exp Biol Med (Maywood) 2021; 246:560-571. [PMID: 33243007 PMCID: PMC7934150 DOI: 10.1177/1535370220975206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 10/30/2020] [Indexed: 12/31/2022] Open
Abstract
Identification of molecular subtypes of clinically resectable triple-negative breast cancer (TNBC) is of great importance to achieve better clinical outcomes. Inter- and intratumor metabolic heterogeneity improves cancer survival, and the interaction of various metabolic pathways may affect treatment outcome of TNBC. We speculated that TNBC can be categorized into prognostic metabolic subtype according to the expression changes of glycolysis and cholesterol synthesis. The genome, transcriptome, and clinical data were downloaded from the Cancer Genome Atlas and Molecular Taxonomy of Breast Cancer International Consortium and subsequently analyzed by integrated bioinformatics methods. Four subtypes, namely, glycolytic, cholesterogenic, quiescent, and mixed, were classified according to the normalized median expressions of the genes involved in glycolysis and cholesterol synthesis. In the four subtypes, the cholesterogenic type was correlated with the shortest median survival (log rank P = 0.044), while patients with high-expressed glycolytic genes tended to have a longer survival. Tumors with PIK3CA amplification and dynein axonemal heavy chain 2 deletion exhibited higher expressions of cholesterogenic genes than other mutant oncogenes. The expressions of mitochondrial pyruvate carrier MPC1 and MPC2 were the lowest in quiescent tumor, and MPC2 expression was higher in cholesterogenic tumor compared with glycolytic or quiescent tumor (t-test P < 0.001). Glycolytic and cholesterogenic gene expressions were related to the expressions of prognostic genes in some other types of cancers. Classification of glycolytic and cholesterogenic pathways according to metabolic characteristics provides a new understanding to previously identified subtypes of TNBC and could improve personalized treatments based on tumor metabolic profiles.
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Affiliation(s)
- Peng-Cheng Zhong
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Rong Shu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Hui-Wen Wu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Zhi-Wen Liu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Xiao-Ling Shen
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
| | - Ying-Jie Hu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510405, China
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20
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Guerra B, Recio C, Aranda-Tavío H, Guerra-Rodríguez M, García-Castellano JM, Fernández-Pérez L. The Mevalonate Pathway, a Metabolic Target in Cancer Therapy. Front Oncol 2021; 11:626971. [PMID: 33718197 PMCID: PMC7947625 DOI: 10.3389/fonc.2021.626971] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 01/18/2021] [Indexed: 12/12/2022] Open
Abstract
A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.
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Affiliation(s)
- Borja Guerra
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Carlota Recio
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Haidée Aranda-Tavío
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Miguel Guerra-Rodríguez
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - José M García-Castellano
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
| | - Leandro Fernández-Pérez
- Molecular and Translational Pharmacology Lab, Institute for Biomedical and Health Research (IUIBS), University of Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
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21
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Yu R, Longo J, van Leeuwen JE, Zhang C, Branchard E, Elbaz M, Cescon DW, Drake RR, Dennis JW, Penn LZ. Mevalonate Pathway Inhibition Slows Breast Cancer Metastasis via Reduced N-glycosylation Abundance and Branching. Cancer Res 2021; 81:2625-2635. [PMID: 33602786 DOI: 10.1158/0008-5472.can-20-2642] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 12/21/2020] [Accepted: 02/15/2021] [Indexed: 11/16/2022]
Abstract
Aberrant N-glycan Golgi remodeling and metabolism are associated with epithelial-mesenchymal transition (EMT) and metastasis in patients with breast cancer. Despite this association, the N-glycosylation pathway has not been successfully targeted in cancer. Here, we show that inhibition of the mevalonate pathway with fluvastatin, a clinically approved drug, reduces both N-glycosylation and N-glycan-branching, essential components of the EMT program and tumor metastasis. This indicates novel cross-talk between N-glycosylation at the endoplasmic reticulum (ER) and N-glycan remodeling at the Golgi. Consistent with this cooperative model between the two spatially separated levels of protein N-glycosylation, fluvastatin-induced tumor cell death was enhanced by loss of Golgi-associated N-acetylglucosaminyltransferases MGAT1 or MGAT5. In a mouse model of postsurgical metastatic breast cancer, adjuvant fluvastatin treatment reduced metastatic burden and improved overall survival. Collectively, these data support the immediate repurposing of fluvastatin as an adjuvant therapeutic to combat metastatic recurrence in breast cancer by targeting protein N-glycosylation at both the ER and Golgi. SIGNIFICANCE: These findings show that metastatic breast cancer cells depend on the fluvastatin-sensitive mevalonate pathway to support protein N-glycosylation, warranting immediate clinical testing of fluvastatin as an adjuvant therapy for breast cancer.
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Affiliation(s)
- Rosemary Yu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Joseph Longo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jenna E van Leeuwen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Cunjie Zhang
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Emily Branchard
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Mohamad Elbaz
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - David W Cescon
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Richard R Drake
- Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina
| | - James W Dennis
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. .,Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Linda Z Penn
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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22
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Choi M, Han J, Yang BR, Jang MJ, Kim M, Lee DW, Kim TY, Im SA, Lee HB, Moon HG, Han W, Noh DY, Lee KH. Association of Insulin, Metformin, and Statin with Mortality in Breast Cancer Patients. Cancer Res Treat 2021; 53:65-76. [PMID: 32972040 PMCID: PMC7812023 DOI: 10.4143/crt.2020.430] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 09/22/2020] [Indexed: 12/29/2022] Open
Abstract
PURPOSE This study investigated the association of insulin, metformin, and statin use with survival and whether the association was modified by the hormone receptor status of the tumor in patients with breast cancer. MATERIALS AND METHODS We studied 7,452 patients who had undergone surgery for breast cancer at Seoul National University Hospital from 2008 to 2015 using the nationwide claims database. Exposure was defined as a recorded prescription of each drug within 12 months before the diagnosis of breast cancer. RESULTS Patients with prior insulin or statin use were more likely to be older than 50 years at diagnosis and had a higher comorbidity index than those without it (p < 0.01 for both). The hazard ratio (HR) for death with insulin use was 5.7 (p < 0.01), and the effect was attenuated with both insulin and metformin exposure with an HR of 1.2 (p=0.60). In the subgroup analyses, a heightened risk of death with insulin was further prominent with an HR of 17.9 (p < 0.01) and was offset by co-administration of metformin with an HR of 1.3 (p=0.67) in patients with estrogen receptor (ER)-negative breast cancer. Statin use was associated with increased overall mortality only in patients with ER-positive breast cancer with HR for death of 1.5 (p=0.05). CONCLUSION Insulin or statin use before the diagnosis of breast cancer was associated with an increase in all-cause mortality. Subsequent analyses suggested that metformin or statin use may have been protective in patients with ER-negative disease, which warrants further studies.
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Affiliation(s)
- Mihong Choi
- Department of Internal Medicine, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon,
Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
| | - Jiyeon Han
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul,
Korea
| | - Bo Ram Yang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul,
Korea
| | - Myoung-jin Jang
- Medical Research Collaborating Center, Seoul National University Hospital, Seoul,
Korea
| | - Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
- Cancer Research Institute, Seoul National University, Seoul,
Korea
| | - Dae-Won Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
- Cancer Research Institute, Seoul National University, Seoul,
Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
- Cancer Research Institute, Seoul National University, Seoul,
Korea
| | - Han-Byoel Lee
- Department of Surgery, Seoul National University Hospital, Seoul,
Korea
| | - Hyeong-Gon Moon
- Department of Surgery, Seoul National University Hospital, Seoul,
Korea
| | - Wonshik Han
- Department of Surgery, Seoul National University Hospital, Seoul,
Korea
| | - Dong-Young Noh
- Department of Surgery, Seoul National University Hospital, Seoul,
Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul,
Korea
- Cancer Research Institute, Seoul National University, Seoul,
Korea
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23
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Ahmadi M, Amiri S, Pecic S, Machaj F, Rosik J, Łos MJ, Alizadeh J, Mahdian R, da Silva Rosa SC, Schaafsma D, Shojaei S, Madrakian T, Zeki AA, Ghavami S. Pleiotropic effects of statins: A focus on cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165968. [PMID: 32927022 DOI: 10.1016/j.bbadis.2020.165968] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/21/2020] [Accepted: 09/07/2020] [Indexed: 02/07/2023]
Abstract
The statin drugs ('statins') potently inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease de novo cholesterol biosynthesis and thereby reduce plasma cholesterol levels. Statins exhibit "pleiotropic" properties that are independent of their lipid-lowering effects. For example, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. Furthermore, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling. However, whether statins have clinically meaningful anti-cancer effects remains an area of active investigation. Both preclinical and clinical studies on the potential mechanisms of action of statins in several cancers have been reviewed in the literature. Considering the contradictory data on their efficacy, we present an up-to-date summary of the pleiotropic effects of statins in cancer therapy and review their impact on different malignancies. We also discuss the synergistic anti-cancer effects of statins when combined with other more conventional anti-cancer drugs to highlight areas of potential therapeutic development.
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Affiliation(s)
- Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Shayan Amiri
- Division of Neurodegenerative Disorders, St Boniface Hospital Albrechtsen Research Centre, R4046 - 351 Taché Ave, Winnipeg, Manitoba R2H 2A6, Canada; Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada
| | - Stevan Pecic
- Department of Chemistry and Biochemistry, California State University Fullerton, CA, USA
| | - Filip Machaj
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Department of Pathology, Pomeranian Medical University in Szczecin, Poland
| | - Jakub Rosik
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Department of Pathology, Pomeranian Medical University in Szczecin, Poland
| | - Marek J Łos
- Biotechnology Center, Silesian University of Technology, Gliwice, Poland
| | - Javad Alizadeh
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
| | - Reza Mahdian
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
| | | | - Shahla Shojaei
- College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Tayyebeh Madrakian
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Amir A Zeki
- University of California, Davis School of Medicine. Division of Pulmonary, Critical Care, and Sleep Medicine. U.C. Davis Lung Center, Davis, California, USA; Veterans Affairs Medical Center, Mather, California, USA
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada.
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24
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Longo J, van Leeuwen JE, Elbaz M, Branchard E, Penn LZ. Statins as Anticancer Agents in the Era of Precision Medicine. Clin Cancer Res 2020; 26:5791-5800. [PMID: 32887721 DOI: 10.1158/1078-0432.ccr-20-1967] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/29/2020] [Accepted: 09/01/2020] [Indexed: 02/06/2023]
Abstract
Statins are widely prescribed cholesterol-lowering drugs that inhibit HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate metabolic pathway. Multiple lines of evidence indicate that certain cancers depend on the mevalonate pathway for growth and survival, and, therefore, are vulnerable to statin therapy. However, these immediately available, well-tolerated, and inexpensive drugs have yet to be successfully repurposed and integrated into cancer patient care. In this review, we highlight recent advances and outline important considerations for advancing statins to clinical trials in oncology.
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Affiliation(s)
- Joseph Longo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jenna E van Leeuwen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Mohamad Elbaz
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Emily Branchard
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Linda Z Penn
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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25
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The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma. Leukemia 2020; 35:796-808. [PMID: 32665698 PMCID: PMC7359767 DOI: 10.1038/s41375-020-0962-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 07/01/2020] [Indexed: 12/19/2022]
Abstract
Multiple myeloma (MM) is a plasma cell malignancy that is often driven by chromosomal translocations. In particular, patients with t(4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that t(4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in t(4;14)-positive cells. In response to statin treatment, t(4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that t(4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in t(4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the t(4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of t(4;14)-positive disease.
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26
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Mesenchymal subtype neuroblastomas are addicted to TGF-βR2/HMGCR-driven protein geranylgeranylation. Sci Rep 2020; 10:10748. [PMID: 32612149 PMCID: PMC7329873 DOI: 10.1038/s41598-020-67310-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 06/05/2020] [Indexed: 11/09/2022] Open
Abstract
The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery. We found that screening chemical libraries across neuroblastoma (NBL) tumor subtypes for selectively-lethal compounds revealed metabolic dependencies that defined each subtype. Bioactive compounds were screened across cell models of mesenchymal (MESN) and MYCN-amplified (MYCNA) NBL subtypes, which revealed the mevalonate and folate biosynthetic pathways as MESN-selective dependencies. Treatment with lovastatin, a mevalonate biosynthesis inhibitor, selectively inhibited protein prenylation and induced apoptosis in MESN cells, while having little effect in MYCNA lines. Statin sensitivity was driven by HMGCR expression, the rate-limiting enzyme for cholesterol synthesis, which correlated with statin sensitivity across NBL cell lines, thus providing a drug sensitivity biomarker. Comparing expression profiles from sensitive and resistant cell lines revealed a TGFBR2 signaling axis that regulates HMGCR, defining an actionable addiction in that leads to MESN-subtype-dependent apoptotic cell death.
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27
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Elimam H, El-Say KM, Cybulsky AV, Khalil H. Regulation of Autophagy Progress via Lysosomal Depletion by Fluvastatin Nanoparticle Treatment in Breast Cancer Cells. ACS OMEGA 2020; 5:15476-15486. [PMID: 32637822 PMCID: PMC7331036 DOI: 10.1021/acsomega.0c01618] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 06/05/2020] [Indexed: 05/03/2023]
Abstract
Fluvastatin (FLV) is a statin family member that may play a role in modulating a variety of medical disorders such as atherosclerosis and breast cancer. The present study addresses the ability of FLV to modulate the cellular immune response and provides a new nanosized FLV formula (self-nanoemulsifying delivery system, SNED) potentially more effective for suppression of breast cancer development. We monitored autophagic machinery through the expression of microtubule-associated protein 1A/1B-light chain 3 (LC3I/II). Lysosomal activity upon treatment was evaluated by mRNA and protein expression of lysosomal-associated membrane protein 1 (LAMP-1). Mitogen-activated protein kinase (MAPK) signaling and its association with proinflammatory cytokine secretion were assessed in treated cells. Autophagosome formation was significantly increased in cells that were pretreated with FLV-SNED in comparison to FLV-treated cells. Activation of autophagy was accompanied with arrest of LAMP-1 expression, which correlates with lysosomal activity. Simultaneously, both FLV and FLV-SNED activated MAPK signaling and modified interleukin-6 and tumor necrosis factor-α levels in treated cells. These findings indicate that FLV reduces cell viability via depletion of lysosomal activities along with accumulation of autophagosomes leading to disturbance of autophagosome-lysosomal fusion in treated cells. Furthermore, our data reveal the effectiveness of both FLV agents in the modulation of proinflammatory cytokine secretion from treated cells via regulation of MAPK signaling cascades and indicate that FLV-SNED is more efficient than FLV. This study provides new insights into how FLV regulates breast cancer cell viability via modulation of AMPK-mTOR and ERK-mTOR signaling, and through autophagosome formation accompanied by lysosomal degradation.
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Affiliation(s)
- Hanan Elimam
- Department
of Medicine, McGill University Health Centre
Research Institute, McGill University, Montreal, Quebec H4A 3J1, Canada
- Department
of Biochemistry, Faculty of Pharmacy, University
of Sadat City, Sadat
City 32958, Egypt
- . Tel: +20-11-4171-1945
| | - Khalid M. El-Say
- Department
of Pharmaceutics, Faculty of Pharmacy, King
Abdulaziz University, Jeddah 21589, Saudi Arabia
- Department
of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt
| | - Andrey V. Cybulsky
- Department
of Medicine, McGill University Health Centre
Research Institute, McGill University, Montreal, Quebec H4A 3J1, Canada
| | - Hany Khalil
- Department
of Molecular Biology, Genetic Engineering and Biotechnology Research
Institute, University of Sadat City, Sadat City 32958, Egypt
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28
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Longo J, Hamilton RJ, Masoomian M, Khurram N, Branchard E, Mullen PJ, Elbaz M, Hersey K, Chadwick D, Ghai S, Andrews DW, Chen EX, van der Kwast TH, Fleshner NE, Penn LZ. A pilot window-of-opportunity study of preoperative fluvastatin in localized prostate cancer. Prostate Cancer Prostatic Dis 2020; 23:630-637. [PMID: 32203069 PMCID: PMC7655503 DOI: 10.1038/s41391-020-0221-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 02/11/2020] [Accepted: 02/26/2020] [Indexed: 02/07/2023]
Abstract
Background Statins inhibit HMG-CoA reductase, the rate-limiting enzyme of the mevalonate pathway. Epidemiological and pre-clinical evidence support an association between statin use and delayed prostate cancer (PCa) progression. Here, we evaluated the effects of neoadjuvant fluvastatin treatment on markers of cell proliferation and apoptosis in men with localized PCa. Methods Thirty-three men were treated daily with 80 mg fluvastatin for 4–12 weeks in a single-arm window-of-opportunity study between diagnosis of localized PCa and radical prostatectomy (RP) (ClinicalTrials.gov: NCT01992042). Percent Ki67 and cleaved Caspase-3 (CC3)-positive cells in tumor tissues were evaluated in 23 patients by immunohistochemistry before and after treatment. Serum and intraprostatic fluvastatin concentrations were quantified by liquid chromatography-mass spectrometry. Results Baseline characteristics included a median prostate-specific antigen (PSA) level of 6.48 ng/mL (IQR: 4.21–10.33). The median duration of fluvastatin treatment was 49 days (range: 27–102). Median serum low-density lipoprotein levels decreased by 35% after treatment, indicating patient compliance. Median PSA decreased by 12%, but this was not statistically significant in our small cohort. The mean fluvastatin concentration measured in the serum was 0.2 μM (range: 0.0–1.1 μM), and in prostatic tissue was 8.5 nM (range: 0.0–77.0 nM). At these concentrations, fluvastatin induced PCa cell death in vitro in a dose- and time-dependent manner. In patients, fluvastatin treatment did not significantly alter intratumoral Ki67 positivity; however, a median 2.7-fold increase in CC3 positivity (95% CI: 1.9–5.0, p = 0.007) was observed in post-fluvastatin RP tissues compared with matched pre-treatment biopsy controls. In a subset analysis, this increase in CC3 was more pronounced in men on fluvastatin for >50 days. Conclusions Fluvastatin prior to RP achieves measurable drug concentrations in prostatic tissue and is associated with promising effects on tumor cell apoptosis. These data warrant further investigation into the anti-neoplastic effects of statins in prostate tissue.
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Affiliation(s)
- Joseph Longo
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Robert J Hamilton
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, ON, Canada
| | - Mehdi Masoomian
- Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
| | - Najia Khurram
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, ON, Canada
| | - Emily Branchard
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Peter J Mullen
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Mohamad Elbaz
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Karen Hersey
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, ON, Canada
| | - Dianne Chadwick
- Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
| | - Sangeet Ghai
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Joint Department of Medical Imaging, Mount Sinai Hospital & University Health Network, Toronto, ON, Canada
| | - David W Andrews
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.,Sunnybrook Research Institute, Toronto, ON, Canada
| | - Eric X Chen
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Theodorus H van der Kwast
- Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, ON, Canada
| | - Neil E Fleshner
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, ON, Canada.
| | - Linda Z Penn
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. .,Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
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29
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Cholesterol and beyond - The role of the mevalonate pathway in cancer biology. Biochim Biophys Acta Rev Cancer 2020; 1873:188351. [PMID: 32007596 DOI: 10.1016/j.bbcan.2020.188351] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 01/14/2020] [Accepted: 01/30/2020] [Indexed: 02/07/2023]
Abstract
Cancer is a multifaceted global disease. Transformation of a normal to a malignant cell takes several steps, including somatic mutations, epigenetic alterations, metabolic reprogramming and loss of cell growth control. Recently, the mevalonate pathway has emerged as a crucial regulator of tumor biology and a potential therapeutic target. This pathway controls cholesterol production and posttranslational modifications of Rho-GTPases, both of which are linked to several key steps of tumor progression. Inhibitors of the mevalonate pathway induce pleiotropic antitumor-effects in several human malignancies, identifying the pathway as an attractive candidate for novel therapies. In this review, we will provide an overview about the role and regulation of the mevalonate pathway in certain aspects of cancer initiation and progression and its potential for therapeutic intervention in oncology.
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Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, Williamson LM, Wong HL, Lee MKC, O'Kane GM, Moore RA, Mungall AJ, Moore MJ, Warren C, Metcalfe A, Notta F, Knox JJ, Gallinger S, Laskin J, Marra MA, Jones SJM, Renouf DJ, Schaeffer DF. Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer. Clin Cancer Res 2019; 26:135-146. [PMID: 31481506 DOI: 10.1158/1078-0432.ccr-19-1543] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 07/11/2019] [Accepted: 08/28/2019] [Indexed: 11/16/2022]
Abstract
PURPOSE Identification of clinically actionable molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcome. Intertumoral metabolic heterogeneity contributes to cancer survival and the balance between distinct metabolic pathways may influence PDAC outcome. We hypothesized that PDAC can be stratified into prognostic metabolic subgroups based on alterations in the expression of genes involved in glycolysis and cholesterol synthesis. EXPERIMENTAL DESIGN We performed bioinformatics analysis of genomic, transcriptomic, and clinical data in an integrated cohort of 325 resectable and nonresectable PDAC. The resectable datasets included retrospective The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts. The nonresectable PDAC cohort studies included prospective COMPASS, PanGen, and BC Cancer Personalized OncoGenomics program (POG). RESULTS On the basis of the median normalized expression of glycolytic and cholesterogenic genes, four subgroups were identified: quiescent, glycolytic, cholesterogenic, and mixed. Glycolytic tumors were associated with the shortest median survival in resectable (log-rank test P = 0.018) and metastatic settings (log-rank test P = 0.027). Patients with cholesterogenic tumors had the longest median survival. KRAS and MYC-amplified tumors had higher expression of glycolytic genes than tumors with normal or lost copies of the oncogenes (Wilcoxon rank sum test P = 0.015). Glycolytic tumors had the lowest expression of mitochondrial pyruvate carriers MPC1 and MPC2. Glycolytic and cholesterogenic gene expression correlated with the expression of prognostic PDAC subtype classifier genes. CONCLUSIONS Metabolic classification specific to glycolytic and cholesterogenic pathways provides novel biological insight into previously established PDAC subtypes and may help develop personalized therapies targeting unique tumor metabolic profiles.See related commentary by Mehla and Singh, p. 6.
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Affiliation(s)
| | | | - Steve E Kalloger
- Pancreas Centre BC, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Gun Ho Jang
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | | | - Luka Culibrk
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
| | - Laura M Williamson
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
| | - Hui-Li Wong
- Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Michael K C Lee
- Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Grainne M O'Kane
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Richard A Moore
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
| | - Andrew J Mungall
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
| | - Malcolm J Moore
- Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Cassia Warren
- Pancreas Centre BC, Vancouver, British Columbia, Canada
| | | | - Faiyaz Notta
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Jennifer J Knox
- University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Steven Gallinger
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada.,University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Janessa Laskin
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.,Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Steven J M Jones
- Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.,Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daniel J Renouf
- Pancreas Centre BC, Vancouver, British Columbia, Canada.,Division of Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.,Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - David F Schaeffer
- Pancreas Centre BC, Vancouver, British Columbia, Canada. .,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada
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Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay. Sci Rep 2019; 9:10278. [PMID: 31311976 PMCID: PMC6635484 DOI: 10.1038/s41598-019-46531-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 06/26/2019] [Indexed: 12/15/2022] Open
Abstract
Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P+ cells with FGF2 stimulates growth in ultra-low attachment conditions analogous to growth in the soft agar. This transformation HTS identified picropodophyllin, an insulin growth factor 1 receptor (IGF1R) inhibitor, and fluvastatin, an HMG-CoA reductase inhibitor, as potential chemopreventive agents. These compounds were validated for efficacy using two non-tumorigenic cell lines in soft agar. Another IGF1R inhibitor and other statins were also tested and several were able to inhibit growth in soft agar. This novel 3D HTS platform is fast, robust and has the potential to identify agents for obesity-associated cancer prevention.
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Sherbet GV. Statins: A Conceivable Remedial Role for the Regulation of Cancer Progression. CURRENT CANCER THERAPY REVIEWS 2019. [DOI: 10.2174/1573394714666180611113834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The mevalonate pathway (also known as the cholesterol biosynthesis pathway) plays a crucial metabolic role in normal cell function as well as in the pathological environment. It leads to the synthesis of sterol and non-sterol isoprenoid biomolecules which subserve a variety of cellular functions. It is known to be deregulated in many disease processes. Statins and bisphosphonates are prominent inhibitors of the mevalonate pathway. They inhibit cell proliferation and activate apoptotic signalling and suppress tumour growth. Statins subdue metastatic spread of tumours by virtue of their ability to suppress invasion and angiogenesis. The induction of autophagy is another feature of statin effects that could contribute to the suppression of metastasis. Herein highlighted are the major signalling systems that statins engage to generate these biological effects. Statins can constrain tumour growth by influencing the expression and function of growth factor and receptor systems. They may suppress epithelial mesenchymal transition with resultant inhibition of cell survival signalling, together with the inhibition of cancer stem cell generation, and their maintenance and expansion. They can suppress ER (oestrogen receptor)-α in breast cancer cells. Statins have been implicated in the activation of the serine/threonine protein kinase AMPK (5' adenosine monophosphate-activated protein) leading to the suppression of cell proliferation. Both statins and bisphosphonates can suppress angiogenic signalling by HIF (hypoxia- inducible factor)-1/eNOS (endothelial nitric oxide synthase) and VEGF (vascular endothelial growth factor)/VEGFR (VEGF receptor). Statins have been linked with improvements in disease prognosis. Also attributed to them is the ability of cancer prevention and reduction of risk of some forms of cancer. The wide spectrum of cancer associated events which these mevalonate inhibitors appear to influence would suggest a conceivable role for them in cancer management. However, much deliberation is warranted in the design and planning of clinical trials, their scope and definition of endpoints, modes risk assessment and the accrual of benefits.
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Affiliation(s)
- Gajanan V. Sherbet
- School of Engineering, University of Newcastle Upon Tyne, Newcastle Upon Tyne, NE2 4HH, United Kingdom
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An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer. Mol Metab 2019; 25:119-130. [PMID: 31023626 PMCID: PMC6600047 DOI: 10.1016/j.molmet.2019.04.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/27/2019] [Accepted: 04/02/2019] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death. METHODS Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry. RESULTS High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells. CONCLUSION Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.
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Göbel A, Breining D, Rauner M, Hofbauer LC, Rachner TD. Induction of 3-hydroxy-3-methylglutaryl-CoA reductase mediates statin resistance in breast cancer cells. Cell Death Dis 2019; 10:91. [PMID: 30692522 PMCID: PMC6349912 DOI: 10.1038/s41419-019-1322-x] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/18/2018] [Accepted: 01/07/2019] [Indexed: 12/15/2022]
Abstract
The mevalonate pathway has emerged as a promising target for several solid tumors. Statins are inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the rate-limiting enzyme of this pathway, and are commonly used to treat patients with hypercholesterolemia. Pleiotropic antitumor mechanisms of statins have been demonstrated for several human cancer types. However, cancer cells differ in their individual statin sensitivity and some cell lines have shown relative resistance. In this study we demonstrate, that the human breast cancer cell lines MDA-MB-231, MDA-MB-468, MCF-7, and T47D are differentially affected by statins. Whereas the vitality of MDA-MB-231 and MDA-MB-468 cells was reduced by up to 60% using atorvastatin, simvastatin, or rosuvastatin (p < 0.001), only marginal effects were seen in T47D and MCF-7 cells following exposure to statins. Statin treatment led to an upregulation of HMGCR mRNA and protein expression by up to sixfolds in the statin-resistant cells lines (p < 0.001), but no alterations of HMGCR were observed in the statin-sensitive MDA-MB-231 and MDA-MB-468 cells. The knockdown of HMGCR prior to statin treatment sensitized the resistant cell lines, reflected by a 70% reduction in vitality, increased apoptotic DNA fragmentation (sixfold) and by accumulation of the apoptosis marker cleaved poly-ADP ribose polymerase. Statins induced a cleavage of the sterol-regulatory element-binding protein (SREBP)-2, a transcriptional activator of the HMGCR, in T47D and MCF-7 cells. The inhibition of SREBP-2 activation by co-administration of dipyridamole sensitized MCF-7 and T47D cells for statins (loss of vitality by 80%; p < 0.001). Furthermore, assessment of a statin-resistant MDA-MB-231 clone, generated by long-term sublethal statin exposure, revealed a significant induction of HMGCR expression by up to 12-folds (p < 0.001). Knockdown of HMGCR restored statin sensitivity back to levels of the parental cells. In conclusion, these results indicate a resistance of cancer cells against statins, which is in part due to the induction of HMGCR.
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Affiliation(s)
- Andy Göbel
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany. .,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
| | - Dorit Breining
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany
| | - Martina Rauner
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Lorenz C Hofbauer
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany
| | - Tilman D Rachner
- Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany
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35
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Immunoliposomes with Simvastatin as a Potential Therapeutic in Treatment of Breast Cancer Cells Overexpressing HER2-An In Vitro Study. Cancers (Basel) 2018; 10:cancers10110418. [PMID: 30388834 PMCID: PMC6266203 DOI: 10.3390/cancers10110418] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/22/2018] [Accepted: 10/30/2018] [Indexed: 12/16/2022] Open
Abstract
Lipophilic statins are promising candidates for breast cancer treatment. However, anticancer therapy requires much higher doses of statins than can be delivered orally, and such high doses are known to exert more adverse effects. The main objective of our study was to design a targeted, therapeutic liposomal carrier of simvastatin characterised by high stability and specificity towards breast cancer cells. We chose SKBR3, the cell line that showed the highest sensitivity for simvastatin and liposomal simvastatin treatment. Additionally, SKBR3 has a notably high expression level of human epidermal growth factor receptor 2 (HER2), which we used as a target for our immunoliposomes. To do so we attached humanized anti-HER2 antibody to the envelope of liposomes. We tested the stability and selectivity of the proposed formulation along with the toxicity, ability to induce apoptosis and the effect on signalling pathways involving Akt and Erk kinases. The immunoliposomal formulation of simvastatin is characterized by long-term stability, high selectivity towards HER2-overexpressing breast cancer cells, low non-specific cytotoxicity and effective inhibition of the growth of target cells, presumably by inhibition of signalling pathways and induction of apoptosis. Hence, for the first time, we propose the use of immunoliposomes with simvastatin, targeted directly towards breast cancer cells overexpressing HER2. The prepared immunoliposomes may become a proof of concept in developing new anticancer therapy.
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36
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El Sayed I, Helmy MW, El-Abhar HS. Inhibition of SRC/FAK cue: A novel pathway for the synergistic effect of rosuvastatin on the anti-cancer effect of dasatinib in hepatocellular carcinoma. Life Sci 2018; 213:248-257. [PMID: 30292831 DOI: 10.1016/j.lfs.2018.10.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Revised: 09/20/2018] [Accepted: 10/03/2018] [Indexed: 01/01/2023]
Abstract
PURPOSE Statins extended their hypocholestremic effect to show a promising anticancer activity. Hepatocellular carcinoma (HCC), the third common cause of cancer-related death, responded positively to statins. Some in-vitro studies reveal the rosuvastatin antitumor effect, but barely in-vivo studies. Hence, we evaluated the antitumor potential of rosuvastatin in a HCC model, the possible signaling cues involved, and whether it augments the dasatinib anticancer effect. METHOD For the in-vitro study, the IC50 and the combination (CI)/dose reduction (DRI) indices were determined for HCC cell line (HepG2) treated with dasatinib and/or rosuvastatin. For the in-vivo study, mice with diethylnitrosamine-induced HCC were treated for 21 days with dasatinib and/or rosuvastatin (10 and 20 mg/kg, respectively). The p-focal adhesion kinase/p-rous sarcoma oncogene cellular homolog (p-FAK/p-Src) cascade and its downstream molecules were assessed. RESULTS The in-vitro study confirmed the synergistic effect of rosuvastatin with dasatinib, which entailed the in-vivo results. The two drugs decreased the p-FAK/p-Src cue along with p-Ras/c-Raf, p-STAT-3, and p-Akt levels to enhance apoptosis by an increase in caspase-3 level and a decline in survivin level. Additionally, they inhibited HGF, VEGF, and the MMP-9. Moreover, the different treatments downregulated the expression of proliferative cell nuclear antigen (PCNA) and Ki-67. The best effect was mediated by the combination regimen that surpassed the effect of either drug alone. CONCLUSION Our results highlighted some of the signals involved in rosuvastatin antitumor effect and nominate it as an adds-on therapy with dasatinib to yield a better effect in HCC through inhibiting the FAK/Src cascade.
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Affiliation(s)
- Ibrahim El Sayed
- Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Maged W Helmy
- Pharmacology and Toxicology, Faculty of Pharmacy, Damanhour University, El-Bahira, Egypt.
| | - Hanan S El-Abhar
- Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
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Abdullah MI, de Wolf E, Jawad MJ, Richardson A. The poor design of clinical trials of statins in oncology may explain their failure - Lessons for drug repurposing. Cancer Treat Rev 2018; 69:84-89. [PMID: 29936313 DOI: 10.1016/j.ctrv.2018.06.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 06/14/2018] [Accepted: 06/15/2018] [Indexed: 01/27/2023]
Abstract
Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an "undruggable" target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.
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Affiliation(s)
- Marwan I Abdullah
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, United Kingdom
| | - Elizabeth de Wolf
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, United Kingdom
| | - Mohammed J Jawad
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, United Kingdom
| | - Alan Richardson
- Institute for Science and Technology in Medicine, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, United Kingdom; School of Pharmacy, Guy Hilton Research Centre, Keele University, Thornburrow Drive, Stoke-on-Trent ST4 7QB, United Kingdom.
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38
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Fry EA, Inoue K. Aberrant expression of ETS1 and ETS2 proteins in cancer. CANCER REPORTS AND REVIEWS 2018; 2:10.15761/CRR.1000151. [PMID: 29974077 PMCID: PMC6027756 DOI: 10.15761/crr.1000151] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The ETS transcription factors regulate expression of genes involved in normal cell development, proliferation, differentiation, angiogenesis, and apoptosis, consisting of 28 family members in humans. Dysregulation of these transcription factors facilitates cell proliferation in cancers, and several members participate in invasion and metastasis by activating gene transcription. ETS1 and ETS2 are the founding members of the ETS family and regulate transcription by binding to ETS sequences. They are both involved in oncogenesis and tumor suppression depending on the biological situations used. The essential roles of ETS proteins in human telomere maintenance have been suggested, which have been linked to creation of new Ets binding sites. Recently, preferential binding of ETS2 to gain-of-function mutant p53 and ETS1 to wild type p53 (WTp53) has been suggested, raising the tumor promoting role for the former and tumor suppressive role for the latter. The oncogenic and tumor suppressive functions of ETS1 and 2 proteins have been discussed.
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Affiliation(s)
- Elizabeth A. Fry
- The Dept. of Pathology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 USA
| | - Kazushi Inoue
- The Dept. of Pathology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157 USA
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Lettiero B, Inasu M, Kimbung S, Borgquist S. Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells. Sci Rep 2018; 8:5462. [PMID: 29615666 PMCID: PMC5882899 DOI: 10.1038/s41598-018-23726-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 03/12/2018] [Indexed: 12/12/2022] Open
Abstract
Apart from the relevant lipid-lowering effects, statins have demonstrated significant, although heterogeneous, anti-tumor activities in preventing breast cancer (BC) progression. To characterize the critical pathways behind the diverse responses to therapy, we investigated statin-induced changes in regulation of lipid metabolism and abundance of neutral lipid-containing cytoplasmic lipid droplets (LDs) in BC cells displaying different sensitivity to atorvastatin. Following atorvastatin treatment, accumulated LD levels inversely mirrored the marginal anti-proliferative effects in a dose and time-dependent manner in the less-sensitive BC cells. Transcriptional profiling excluded dysregulation of lipid uptake and efflux as specific mechanisms associated with differences in LD accumulation and anti-proliferative effects of atorvastatin. Notably, significant upregulation of genes involved in unsaturated fatty acid metabolism [stearoyl-CoA desaturase (SCD)] and cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], were associated with atorvastatin insensitivity. Taken together, the increased ability to store neutral lipids in LDs as consequence of atorvastatin treatment likely confers a proliferative advantage to BC cells and may serve as potential biomarker of statin resistance in BC. Contributions of cholesterol biosynthesis and unsaturated fatty acid metabolism to LD formation should be thoroughly explored for better understanding of the molecular mechanisms underlying statin-induced effects against BC progression.
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Affiliation(s)
- Barbara Lettiero
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Maria Inasu
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Siker Kimbung
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Signe Borgquist
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden. .,Clinical Trial Unit, Skåne University Hospital, Lund, Sweden.
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Relationship of SNP rs2645429 in Farnesyl-Diphosphate Farnesyltransferase 1 Gene Promoter with Susceptibility to Lung Cancer. Int J Genomics 2018; 2018:4863757. [PMID: 29765975 PMCID: PMC5885393 DOI: 10.1155/2018/4863757] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Revised: 02/05/2018] [Accepted: 02/14/2018] [Indexed: 12/15/2022] Open
Abstract
Background and Purpose The mevalonate pathway is one of the major metabolic pathways that use acetyl-CoA to produce sterols and isoprenoids. These compounds can be effective in the growth and development of tumors. One of the enzymes involved in the mevalonate pathway is FDFT1. Different variants of this gene are involved in the risk of suffering various diseases. The present study examined the relationship between FDFT1 rs2645429 polymorphism and the risk of nonsmall cell lung cancer (NSCLC) in a population from southern Iran. Method The genotypes of rs2645429 polymorphism of FDFT1 gene were examined in 95 samples: 34 patients with NSCLC and 61 healthy individuals by RFLP method. Results The results of this study indicated that C allele of this polymorphism was effectively associated with the risk of NSCLC in the Iranian population (p value = 0.023; OR = 2.71; 95% CI = 1.12–6.59) and CC genotype has significant relation with susceptibility to NSCLC (p value = 0.029; OR = 3.02; 95% CI = 1.09–8.39). This polymorphism is located in the promoter region FDFT1 gene, and CC genotype may increase the activity of this promoter. This study also found a significant relationship between C allele and metastatic status. C allele was more common in NSCLC patients. (p = 0.04). Conclusion C allele of FDFT1 rs2645429 polymorphism gene can be a risk factor for NSCLC, whereas T allele probably has a low protective role.
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Kimbung S, Lettiero B, Feldt M, Bosch A, Borgquist S. High expression of cholesterol biosynthesis genes is associated with resistance to statin treatment and inferior survival in breast cancer. Oncotarget 2018; 7:59640-59651. [PMID: 27458152 PMCID: PMC5312337 DOI: 10.18632/oncotarget.10746] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 07/10/2016] [Indexed: 01/12/2023] Open
Abstract
There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.
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Affiliation(s)
- Siker Kimbung
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Barbara Lettiero
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Maria Feldt
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Ana Bosch
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Oncology, Skåne University Hospital, Lund, Sweden
| | - Signe Borgquist
- Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Oncology, Skåne University Hospital, Lund, Sweden
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Yu R, Longo J, van Leeuwen JE, Mullen PJ, Ba-Alawi W, Haibe-Kains B, Penn LZ. Statin-Induced Cancer Cell Death Can Be Mechanistically Uncoupled from Prenylation of RAS Family Proteins. Cancer Res 2017; 78:1347-1357. [PMID: 29229608 DOI: 10.1158/0008-5472.can-17-1231] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 10/04/2017] [Accepted: 11/30/2017] [Indexed: 11/16/2022]
Abstract
The statin family of drugs preferentially triggers tumor cell apoptosis by depleting mevalonate pathway metabolites farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are used for protein prenylation, including the oncoproteins of the RAS superfamily. However, accumulating data indicate that activation of the RAS superfamily are poor biomarkers of statin sensitivity, and the mechanism of statin-induced tumor-specific apoptosis remains unclear. Here we demonstrate that cancer cell death triggered by statins can be uncoupled from prenylation of the RAS superfamily of oncoproteins. Ectopic expression of different members of the RAS superfamily did not uniformly sensitize cells to fluvastatin, indicating that increased cellular demand for protein prenylation cannot explain increased statin sensitivity. Although ectopic expression of HRAS increased statin sensitivity, expression of myristoylated HRAS did not rescue this effect. HRAS-induced epithelial-to-mesenchymal transition (EMT) through activation of zinc finger E-box binding homeobox 1 (ZEB1) sensitized tumor cells to the antiproliferative activity of statins, and induction of EMT by ZEB1 was sufficient to phenocopy the increase in fluvastatin sensitivity; knocking out ZEB1 reversed this effect. Publicly available gene expression and statin sensitivity data indicated that enrichment of EMT features was associated with increased sensitivity to statins in a large panel of cancer cell lines across multiple cancer types. These results indicate that the anticancer effect of statins is independent from prenylation of RAS family proteins and is associated with a cancer cell EMT phenotype.Significance: The use of statins to target cancer cell EMT may be useful as a therapy to block cancer progression. Cancer Res; 78(5); 1347-57. ©2017 AACR.
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Affiliation(s)
- Rosemary Yu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Joseph Longo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Jenna E van Leeuwen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Peter J Mullen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Wail Ba-Alawi
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
- Ontario Institute of Cancer Research, Toronto, Ontario, Canada
| | - Linda Z Penn
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Hamilton RJ. Making Sense of the Statin-Prostate Cancer Relationship: Is It Time for a Randomized Controlled Trial? Eur Urol Focus 2017; 3:221-222. [PMID: 28753767 DOI: 10.1016/j.euf.2016.06.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 06/13/2016] [Indexed: 12/01/2022]
Affiliation(s)
- Robert J Hamilton
- Division of Urology, Departments of Surgical Oncology, Princess Margaret Cancer Centre, University Health Network and the University of Toronto, Toronto, Canada.
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Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer. Sci Rep 2017; 7:5410. [PMID: 28710496 PMCID: PMC5511264 DOI: 10.1038/s41598-017-05595-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 06/05/2017] [Indexed: 12/14/2022] Open
Abstract
Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins.
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Borgquist S, Giobbie-Hurder A, Ahern TP, Garber JE, Colleoni M, Láng I, Debled M, Ejlertsen B, von Moos R, Smith I, Coates AS, Goldhirsch A, Rabaglio M, Price KN, Gelber RD, Regan MM, Thürlimann B. Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study. J Clin Oncol 2017; 35:1179-1188. [DOI: 10.1200/jco.2016.70.3116] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Purpose Cholesterol-lowering medication (CLM) has been reported to have a role in preventing breast cancer recurrence. CLM may attenuate signaling through the estrogen receptor by reducing levels of the estrogenic cholesterol metabolite 27-hydroxycholesterol. The impact of endocrine treatment on cholesterol levels and hypercholesterolemia per se may counteract the intended effect of aromatase inhibitors. Patients and Methods The Breast International Group (BIG) conducted a randomized, phase III, double-blind trial, BIG 1-98, which enrolled 8,010 postmenopausal women with early-stage, hormone receptor–positive invasive breast cancer from 1998 to 2003. Systemic levels of total cholesterol and use of CLM were measured at study entry and every 6 months up to 5.5 years. Cumulative incidence functions were used to describe the initiation of CLM in the presence of competing risks. Marginal structural Cox proportional hazards modeling investigated the relationships between initiation of CLM during endocrine therapy and outcome. Three time-to-event end points were considered: disease-free-survival, breast cancer–free interval, and distant recurrence–free interval. Results Cholesterol levels were reduced during tamoxifen therapy. Of 789 patients who initiated CLM during endocrine therapy, the majority came from the letrozole monotherapy arm (n = 318), followed by sequential tamoxifen-letrozole (n = 189), letrozole-tamoxifen (n = 176), and tamoxifen monotherapy (n = 106). Initiation of CLM during endocrine therapy was related to improved disease-free-survival (hazard ratio [HR], 0.79; 95% CI, 0.66 to 0.95; P = .01), breast cancer–free interval (HR, 0.76; 95% CI, 0.60 to 0.97; P = .02), and distant recurrence–free interval (HR, 0.74; 95% CI, 0.56 to 0.97; P = .03). Conclusion Cholesterol-lowering medication during adjuvant endocrine therapy may have a role in preventing breast cancer recurrence in hormone receptor–positive early-stage breast cancer. We recommend that these observational results be addressed in prospective randomized trials.
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Affiliation(s)
- Signe Borgquist
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Anita Giobbie-Hurder
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Thomas P. Ahern
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Judy E. Garber
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Marco Colleoni
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - István Láng
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Marc Debled
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Bent Ejlertsen
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Roger von Moos
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Ian Smith
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Alan S. Coates
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Aron Goldhirsch
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Manuela Rabaglio
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Karen N. Price
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Richard D. Gelber
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Meredith M. Regan
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
| | - Beat Thürlimann
- Signe Borgquist and Judy E. Garber, Dana-Farber Cancer Institute, Harvard Medical School; Anita Giobbie-Hurder, International Breast Cancer Study Group (IBCSG) Statistical Center, Dana-Farber Cancer Institute; Richard D. Gelber, IBCSG Statistical Center, Dana-Farber Cancer Institute, Harvard Medical School, T.H. Chan Harvard School of Public Health, and Frontier Science and Technology Research Foundation; Karen N. Price, IBCSG Statistical Center and Frontier Science and Technology Research Foundation
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Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells. Sci Rep 2017; 7:44841. [PMID: 28344327 PMCID: PMC5366866 DOI: 10.1038/srep44841] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 02/14/2017] [Indexed: 12/21/2022] Open
Abstract
The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.
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Yao H, He G, Yan S, Chen C, Song L, Rosol TJ, Deng X. Triple-negative breast cancer: is there a treatment on the horizon? Oncotarget 2017; 8:1913-1924. [PMID: 27765921 PMCID: PMC5352107 DOI: 10.18632/oncotarget.12284] [Citation(s) in RCA: 271] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 09/17/2016] [Indexed: 12/28/2022] Open
Abstract
Triple-negative breast cancer (TNBC), which accounts for 15-20% of all breast cancers, does not express estrogen receptor (ER) or progesterone receptor (PR) and lacks human epidermal growth factor receptor 2 (HER2) overexpression or amplification. These tumors have a more aggressive phenotype and a poorer prognosis due to the high propensity for metastatic progression and absence of specific targeted treatments. Patients with TNBC do not benefit from hormonal or trastuzumab-based targeted therapies because of the loss of target receptors. Although these patients respond to chemotherapeutic agents such as taxanes and anthracyclines better than other subtypes of breast cancer, prognosis remains poor. A group of targeted therapies under investigation showed favorable results in TNBC, especially in cancers with BRCA mutation. The lipid-lowering statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors), including lovastatin and simvastatin, have been shown to preferentially target TNBC compared with non-TNBC. These statins hold great promise for the management of TNBC. Only with the understanding of the molecular basis for the preference of statins for TNBC and more investigations in clinical trials can they be reformulated into a clinically approved drug against TNBC.
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Affiliation(s)
- Hui Yao
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan, China
| | - Guangchun He
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan, China
| | - Shichao Yan
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan, China
| | - Chao Chen
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan, China
| | - Liujiang Song
- Department of Pediatrics, Hunan Normal University Medical College, Changsha, Hunan, China
| | - Thomas J. Rosol
- Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio, USA
| | - Xiyun Deng
- Department of Pathology, Hunan Normal University Medical College, Changsha, Hunan, China
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48
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Mullen PJ, Yu R, Longo J, Archer MC, Penn LZ. The interplay between cell signalling and the mevalonate pathway in cancer. Nat Rev Cancer 2016; 16:718-731. [PMID: 27562463 DOI: 10.1038/nrc.2016.76] [Citation(s) in RCA: 474] [Impact Index Per Article: 52.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The mevalonate (MVA) pathway is an essential metabolic pathway that uses acetyl-CoA to produce sterols and isoprenoids that are integral to tumour growth and progression. In recent years, many oncogenic signalling pathways have been shown to increase the activity and/or the expression of MVA pathway enzymes. This Review summarizes recent advances and discusses unique opportunities for immediately targeting this metabolic vulnerability in cancer with agents that have been approved for other therapeutic uses, such as the statin family of drugs, to improve outcomes for cancer patients.
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Affiliation(s)
- Peter J Mullen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7
| | - Rosemary Yu
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7
| | - Joseph Longo
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7
| | - Michael C Archer
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 3E2
| | - Linda Z Penn
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 1L7
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada M5G 1L7
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49
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Jung HH, Lee SH, Kim JY, Ahn JS, Park YH, Im YH. Statins affect ETS1-overexpressing triple-negative breast cancer cells by restoring DUSP4 deficiency. Sci Rep 2016; 6:33035. [PMID: 27604655 PMCID: PMC5015082 DOI: 10.1038/srep33035] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 08/17/2016] [Indexed: 12/13/2022] Open
Abstract
We investigated the molecular mechanisms underlying statin-induced growth suppression of triple-negative breast cancer (TNBC) that overexpress the transcription factor ets proto-oncogene 1(ets-1) and downregulate dual specific protein phosphatase 4(dusp4) expression. We examined the gene expression of BC cell lines using the nCounter expression assay, MTT viability assay, cell proliferation assay and Western blot to evaluate the effects of simvastatin. Finally, we performed cell viability testing in TNBC cell line-transfected DUSP4. We demonstrated that ETS1 mRNA and protein were overexpressed in TNBC cells compared with other BC cell lines (P = <0.001) and DUSP4 mRNA was downregulated (P = <0.001). MTT viability assay showed that simvastatin had significant antitumor activity (P = 0.002 in 0.1 μM). In addition, simvastatin could restore dusp4 deficiency and suppress ets-1 expression in TNBC. Lastly, we found that si-DUSP4 RNA transfection overcame the antitumor activity of statins. MAPK pathway inhibitor, U0126 and PI3KCA inhibitor LY294002 also decreased levels of ets-1, phosphor-ERK and phosphor-AKT on Western blot assay. Accordingly, our study indicates that simvastatin potentially affects the activity of transcriptional factors such as ets-1 and dusp4 through the MAPK pathway. In conclusion, statins might be potential candidates for TNBC therapy reducing ets-1 expression via overexpression of dusp4.
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Affiliation(s)
- Hae Hyun Jung
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea
| | - Soo-Hyeon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Ji-Yeon Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea
| | - Yeon Hee Park
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul 06351, Korea.,Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.,Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea
| | - Young-Hyuck Im
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea.,Biomedical Research Institute, Samsung Medical Center, Seoul 06351, Korea
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50
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Genome-wide RNAi analysis reveals that simultaneous inhibition of specific mevalonate pathway genes potentiates tumor cell death. Oncotarget 2016; 6:26909-21. [PMID: 26353928 PMCID: PMC4694962 DOI: 10.18632/oncotarget.4817] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/12/2015] [Indexed: 01/03/2023] Open
Abstract
The mevalonate (MVA) pathway is often dysregulated or overexpressed in many cancers suggesting tumor dependency on this classic metabolic pathway. Statins, which target the rate-limiting enzyme of this pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), are promising agents currently being evaluated in clinical trials for anti-cancer efficacy. To uncover novel targets that potentiate statin-induced apoptosis when knocked down, we carried out a pooled genome-wide short hairpin RNA (shRNA) screen. Genes of the MVA pathway were amongst the top-scoring targets, including sterol regulatory element binding transcription factor 2 (SREBP2), 3-hydroxy-3-methylglutaryl-coenzyme A synthase 1 (HMGCS1) and geranylgeranyl diphosphate synthase 1 (GGPS1). Each gene was independently validated and shown to significantly sensitize A549 cells to statin-induced apoptosis when knocked down. SREBP2 knockdown in lung and breast cancer cells completely abrogated the fluvastatin-induced upregulation of sterol-responsive genes HMGCR and HMGCS1. Knockdown of SREBP2 alone did not affect three-dimensional growth of lung and breast cancer cells, yet in combination with fluvastatin cell growth was disrupted. Taken together, these results show that directly targeting multiple levels of the MVA pathway, including blocking the sterol-feedback loop initiated by statin treatment, is an effective and targetable anti-tumor strategy.
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