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Yum C, Andolino C, Layosa MA, Coleman M, Hursting SD, Teegarden D. Differential effects of leptin on energy metabolism in murine cell models of metastatic triple negative breast cancer. Diabetol Metab Syndr 2024; 16:288. [PMID: 39609706 PMCID: PMC11603625 DOI: 10.1186/s13098-024-01535-1] [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: 08/29/2024] [Accepted: 11/17/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND Leptin, an energy balance regulator secreted by adipocytes, increases metastatic potential of breast cancer cells. The impact on cancer cell metabolism remains unclear given that most studies of leptin and breast cancer cell metabolism utilize supraphysiological glucose concentrations. METHODS Using two murine models of metastatic triple-negative breast cancer (TNBC) differing in genetic alterations (4T1: p53 and Pik3ca mutations; metM-Wntlung: increased Wnt signaling) and cultured in physiological (5 mM) glucose media, we tested the hypothesis that leptin increases migration of metastatic breast cancer cells through regulation of glucose metabolism. RESULTS Our results showed that leptin treatment, compared with vehicle, increased cell migration in each cell line, with decreased leptin receptor (Ob-R) mRNA expression in 4T1, but not metM-Wntlung, cells. AMP-activated protein kinase (AMPK) was activated in 4T1 with leptin treatment but decreased in metM-Wntlung. Leptin decreased fatty acid synthase (Fasn) and carnitine palmitoyltransferase 1a (Cpt1a) mRNA expression in 4T1 cells but increased their expression in metM-Wntlung cells. Fatty acid oxidation was not necessary for leptin-induced migration in either cell line. Leptin increased palmitate synthesis from glucose in metM-Wntlung, but not 4T1 cells. Moreover, although leptin increased glucose transporter 1 (Glut1) mRNA expression in both cell lines and inhibition of glycolysis blocked leptin-induced migration in metM-Wntlung, but not 4T1 cells. CONCLUSION Taken together, these results demonstrate that at physiological glucose concentrations, leptin increases migration of 4T1 and metM-Wntlung cells via shared and distinct effects on energy metabolism, suggesting that the type of TNBC genetic alteration plays a role in differential metabolic regulation of leptin-induced migration.
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Affiliation(s)
- Chaehyun Yum
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN, 47907, USA
| | - Chaylen Andolino
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN, 47907, USA
- Purdue University Institute for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Marjorie Anne Layosa
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN, 47907, USA
- Purdue University Institute for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA
| | - Michael Coleman
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, 27516, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27516, USA
| | - Stephen D Hursting
- Department of Nutrition, University of North Carolina, Chapel Hill, NC, 27516, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27516, USA
| | - Dorothy Teegarden
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN, 47907, USA.
- Purdue University Institute for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
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Ghayee HK, Costa KA, Xu Y, Hatch HM, Rodriguez M, Straight SC, Bustamante M, Yu F, Smagulova F, Bowden JA, Tevosian SG. Polyamine Pathway Inhibitor DENSPM Suppresses Lipid Metabolism in Pheochromocytoma Cell Line. Int J Mol Sci 2024; 25:10029. [PMID: 39337514 PMCID: PMC11432427 DOI: 10.3390/ijms251810029] [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: 08/06/2024] [Revised: 09/10/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Pheochromocytomas (PCCs) are tumors arising from chromaffin cells in the adrenal medulla, and paragangliomas (PGLs) are tumors derived from extra-adrenal sympathetic or parasympathetic paraganglia; these tumors are collectively referred to as PPGL cancer. Treatment for PPGL primarily involves surgical removal of the tumor, and only limited options are available for treatment of the disease once it becomes metastatic. Human carriers of the heterozygous mutations in the succinate dehydrogenase subunit B (SDHB) gene are susceptible to the development of PPGL. A physiologically relevant PCC patient-derived cell line hPheo1 was developed, and SDHB_KD cells carrying a stable short hairpin knockdown of SDHB were derived from it. An untargeted metabolomic approach uncovered an overactive polyamine pathway in the SDHB_KD cells that was subsequently fully validated in a large set of human SDHB-mutant PPGL tumor samples. We previously reported that treatment with the polyamine metabolism inhibitor N1,N11-diethylnorspermine (DENSPM) drastically inhibited growth of these PCC-derived cells in culture as well as in xenograft mouse models. Here we explored the mechanisms underlying DENSPM action in hPheo1 and SDHB_KD cells. Specifically, by performing an RNAseq analysis, we have identified gene expression changes associated with DENSPM treatment that broadly interfere with all aspects of lipid metabolism, including fatty acid (FA) synthesis, desaturation, and import/uptake. Furthermore, by performing an untargeted lipidomic liquid chromatography-mass spectrometry (LC/MS)-based analysis we uncovered specific groups of lipids that are dramatically reduced as a result of DENSPM treatment. Specifically, the bulk of plasmanyl ether lipid species that have been recently reported as the major determinants of cancer cell fate are notably decreased. In summary, this work suggests an intersection between active polyamine and lipid pathways in PCC cells.
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Affiliation(s)
- Hans K. Ghayee
- Department of Medicine, Division of Endocrinology, College of Medicine, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL 32608, USA; (Y.X.); (M.B.)
| | - Kaylie A. Costa
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Yiling Xu
- Department of Medicine, Division of Endocrinology, College of Medicine, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL 32608, USA; (Y.X.); (M.B.)
| | - Heather M. Hatch
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Mateo Rodriguez
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Shelby C. Straight
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Marian Bustamante
- Department of Medicine, Division of Endocrinology, College of Medicine, University of Florida and Malcom Randall VA Medical Center, Gainesville, FL 32608, USA; (Y.X.); (M.B.)
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Fahong Yu
- The Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL 32610, USA;
| | - Fatima Smagulova
- Université de Rennes, EHESP, Inserm, Irset (Institut de Recherche en Santé, Environnement et Travail), Campus Sante de Villejean—UMR_S 1085, F-35000 Rennes, France;
| | - John A. Bowden
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
| | - Sergei G. Tevosian
- Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 03610, USA; (K.A.C.); (H.M.H.); (M.R.); (S.C.S.); (J.A.B.)
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Fries BD, Hummon AB. FAS Inhibited Proteomics and Phosphoproteomics Profiling of Colorectal Cancer Spheroids Shows Activation of Ferroptotic Death Mechanism. J Proteome Res 2024; 23:3904-3916. [PMID: 39079039 DOI: 10.1021/acs.jproteome.4c00252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/07/2024]
Abstract
Colorectal cancer (CRC) is projected to become the third most diagnosed and third most fatal cancer in the United States by 2024, with early onset CRC on the rise. Research is constantly underway to discover novel therapeutics for the treatment of various cancers to improve patient outcomes and survival. Fatty acid synthase (FAS) has become a druggable target of interest for the treatment of many different cancers. One such inhibitor, TVB-2640, has gained popularity for its high specificity for FAS and has entered a phase 1 clinical trial for the treatment of solid tumors. However, the distinct molecular differences that occur upon inhibition of FAS have yet to be understood. Here, we conduct proteomics and phosphoproteomics analyses on HCT 116 and HT-29 CRC spheroids inhibited with either a generation 1 (cerulenin) or generation 2 (TVB-2640) FAS inhibitor. Proteins involved in lipid metabolism and cellular respiration were altered in abundance. It was also observed that proteins involved in ferroptosis─an iron mediated form of cell death─were altered. These results show that HT-29 spheroids exposed to cerulenin or TVB-2640 are undergoing a ferroptotic death mechanism. The data were deposited to the ProteomeXchange Consortium via the PRIDE repository with the identifier PXD050987.
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Affiliation(s)
- Brian D Fries
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Amanda B Hummon
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
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Loftus AW, Zarei M, Kakish H, Hajihassani O, Hue JJ, Boutros C, Graor HJ, Nakazzi F, Bahlibi T, Winter JM, Rothermel LD. Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma. Cancer Treat Rev 2024; 129:102795. [PMID: 38972133 PMCID: PMC11361048 DOI: 10.1016/j.ctrv.2024.102795] [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: 04/28/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/09/2024]
Abstract
Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.
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Affiliation(s)
- Alexander W Loftus
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Mehrdad Zarei
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Hanna Kakish
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Omid Hajihassani
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Jonathan J Hue
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Christina Boutros
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA
| | - Hallie J Graor
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Faith Nakazzi
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Tsegaw Bahlibi
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Jordan M Winter
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Luke D Rothermel
- Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, 11100 Euclid Ave., Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
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Fries BD, Tobias F, Wang Y, Holbrook JH, Hummon AB. Lipidomics Profiling Reveals Differential Alterations after FAS Inhibition in 3D Colon Cancer Cell Culture Models. J Proteome Res 2024; 23:2919-2933. [PMID: 38063332 PMCID: PMC11161555 DOI: 10.1021/acs.jproteome.3c00593] [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] [Indexed: 03/21/2024]
Abstract
Cancerous cells synthesize most of their lipids de novo to keep up with their rapid growth and proliferation. Fatty acid synthase (FAS) is a key enzyme in the lipogenesis pathway that is upregulated in many cancers and has gained popularity as a druggable target of interest for cancer treatment. The first FAS inhibitor discovered, cerulenin, initially showed promise for chemotherapeutic purposes until it was observed that it had adverse side effects in mice. TVB-2640 (Denifanstat) is part of the newer generation of inhibitors. With multiple generations of FAS inhibitors being developed, it is vital to understand their distinct molecular downstream effects to elucidate potential interactions in the clinic. Here, we profile the lipidome of two different colorectal cancer (CRC) spheroids treated with a generation 1 inhibitor (cerulenin) or a generation 2 inhibitor (TVB-2640). We observe that the cerulenin causes drastic changes to the spheroid morphology as well as alterations to the lipid droplets found within CRC spheroids. TVB-2640 causes higher abundances of polyunsaturated fatty acids (PUFAs) whereas cerulenin causes a decreased abundance of PUFAs. The increase in PUFAs in TVB-2640 exposed spheroids indicates it is causing cells to die via a ferroptotic mechanism rather than a conventional apoptotic or necrotic mechanism.
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Affiliation(s)
- Brian D Fries
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Fernando Tobias
- Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States
- Integrated Molecular Structure Education and Research Center (IMSERC), Northwestern University, Evanston, Illinois 60208, United States
| | - Yijia Wang
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
| | - Joseph H Holbrook
- Ohio State Biochemistry Program, The Ohio State University, Columbus, Ohio 43210, United States
| | - Amanda B Hummon
- Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States
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Hua S, Wang W, Yao Z, Gu J, Zhang H, Zhu J, Xie Z, Jiang H. The fatty acid-related gene signature stratifies poor prognosis patients and characterizes TIME in cutaneous melanoma. J Cancer Res Clin Oncol 2024; 150:40. [PMID: 38279987 PMCID: PMC10822006 DOI: 10.1007/s00432-023-05580-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/07/2023] [Indexed: 01/29/2024]
Abstract
BACKGROUND The aim of this study is to build a prognostic model for cutaneous melanoma (CM) using fatty acid-related genes and evaluate its capacity for predicting prognosis, identifying the tumor immune microenvironment (TIME) composition, and assessing drug sensitivity. METHODS Through the analysis of transcriptional data from TCGA-SKCM and GTEx datasets, we screened for differentially expressed fatty acids-related genes (DEFAGs). Additionally, we employed clinical data from TCGA-SKCM and GSE65904 to identify genes associated with prognosis. Subsequently, utilizing all the identified prognosis-related fatty acid genes, we performed unsupervised clustering analysis using the ConsensusClusterPlus R package. We further validated the significant differences between subtypes through survival analysis and pathway analysis. To predict prognosis, we developed a LASSO-Cox prognostic signature. This signature's predictive ability was rigorously examined through multivariant Cox regression, survival analysis, and ROC curve analysis. Following this, we constructed a nomogram based on the aforementioned signature and evaluated its accuracy and clinical utility using calibration curves, cumulative hazard rates, and decision curve analysis. Using this signature, we stratified all cases into high- and low-risk groups and compared the differences in immune characteristics and drug treatment responsiveness between these two subgroups. Additionally, in this study, we provided preliminary confirmation of the pivotal role of CD1D in the TIME of CM. We analyzed its expression across various immune cell types and its correlation with intercellular communication using single-cell data from the GSE139249 dataset. RESULTS In this study, a total of 84 DEFAGs were identified, among which 18 were associated with prognosis. Utilizing these 18 prognosis-related genes, all cases were categorized into three subtypes. Significant differences were observed between subtypes in terms of survival outcomes, the expression of the 18 DEFAGs, immune cell proportions, and enriched pathways. A LASSO-Cox regression analysis was performed on these 18 genes, leading to the development of a signature comprising 6 DEFAGs. Risk scores were calculated for all cases, dividing them into high-risk and low-risk groups. High-risk patients exhibited significantly poorer prognosis than low-risk patients, both in the training group (p < 0.001) and the test group (p = 0.002). Multivariate Cox regression analysis indicated that this signature could independently predict outcomes [HR = 2.03 (1.69-2.45), p < 0.001]. The area under the ROC curve for the training and test groups was 0.715 and 0.661, respectively. Combining risk scores with clinical factors including metastatic status and patient age, a nomogram was constructed, which demonstrated significant predictive power for 3 and 5 years patient outcomes. Furthermore, the high and low-risk subgroups displayed differences in the composition of various immune cells, including M1 macrophages, M0 macrophages, and CD8+ T cells. The low-risk subgroup exhibited higher StromalScore, ImmuneScore, and ESTIMATEScore (p < 0.001) and demonstrated better responsiveness to immune therapy for patients with PD1-positive and CTLA4-negative or positive expressions (p < 0.001). The signature gene CD1D was found to be mainly expressed in monocytes/macrophages and dendritic cells within the TIME. Through intercellular communication analysis, it was observed that cases with high CD1D expression exhibited significantly enhanced signal transductions from other immune cells to monocytes/macrophages, particularly the (HLA-A/B/C/E/F)-CD8A signaling from natural killer (NK) cells to monocytes/macrophages (p < 0.01). CONCLUSIONS The prognostic signature constructed in this study, based on six fatty acid-related genes, exhibits strong capabilities in predicting patient outcomes, identifying the TIME, and assessing drug sensitivity. This signature can aid in patient risk stratification and provide guidance for clinical treatment strategies. Additionally, our research highlights the crucial role of CD1D in the CM's TIME, laying a theoretical foundation for future related studies.
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Affiliation(s)
- Shan Hua
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Wenhao Wang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zuochao Yao
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Jiawei Gu
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Hongyi Zhang
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Jie Zhu
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China
| | - Zhiwen Xie
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Jiang
- Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai, 200120, China.
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Tan SK, Hougen HY, Merchan JR, Gonzalgo ML, Welford SM. Fatty acid metabolism reprogramming in ccRCC: mechanisms and potential targets. Nat Rev Urol 2023; 20:48-60. [PMID: 36192502 PMCID: PMC10826284 DOI: 10.1038/s41585-022-00654-6] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2022] [Indexed: 01/11/2023]
Abstract
Lipid droplet formation is a defining histological feature in clear-cell renal cell carcinoma (ccRCC) but the underlying mechanisms and importance of this biological behaviour have remained enigmatic. De novo fatty acid (FA) synthesis, uptake and suppression of FA oxidation have all been shown to contribute to lipid storage, which is a necessary tumour adaptation rather than a bystander effect. Clinical studies and mechanistic investigations into the roles of different enzymes in FA metabolism pathways have revealed new metabolic vulnerabilities that hold promise for clinical effect. Several metabolic alterations are associated with worse clinical outcomes in patients with ccRCC, as lipogenic genes drive tumorigenesis. Enzymes involved in the intrinsic FA metabolism pathway include FA synthase, acetyl-CoA carboxylase, ATP citrate lyase, stearoyl-CoA desaturase 1, cluster of differentiation 36, carnitine palmitoyltransferase 1A and the perilipin family, and each might be potential therapeutic targets in ccRCC owing to the link between lipid deposition and ccRCC risk. Adipokines and lipid species are potential biomarkers for diagnosis and treatment monitoring in patients with ccRCC. FA metabolism could potentially be targeted for therapeutic intervention in ccRCC as small-molecule inhibitors targeting the pathway have shown promising results in preclinical models.
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Affiliation(s)
- Sze Kiat Tan
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA
- Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Helen Y Hougen
- Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jaime R Merchan
- Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Mark L Gonzalgo
- Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA
| | - Scott M Welford
- Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA.
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Bezawork-Geleta A, Dimou J, Watt MJ. Lipid droplets and ferroptosis as new players in brain cancer glioblastoma progression and therapeutic resistance. Front Oncol 2022; 12:1085034. [PMID: 36591531 PMCID: PMC9797845 DOI: 10.3389/fonc.2022.1085034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
A primary brain tumor glioblastoma is the most lethal of all cancers and remains an extremely challenging disease. Apparent oncogenic signaling in glioblastoma is genetically complex and raised at any stage of the disease's progression. Many clinical trials have shown that anticancer drugs for any specific oncogene aberrantly expressed in glioblastoma show very limited activity. Recent discoveries have highlighted that alterations in tumor metabolism also contribute to disease progression and resistance to current therapeutics for glioblastoma, implicating an alternative avenue to improve outcomes in glioblastoma patients. The roles of glucose, glutamine and tryptophan metabolism in glioblastoma pathogenesis have previously been described. This article provides an overview of the metabolic network and regulatory changes associated with lipid droplets that suppress ferroptosis. Ferroptosis is a newly discovered type of nonapoptotic programmed cell death induced by excessive lipid peroxidation. Although few studies have focused on potential correlations between tumor progression and lipid droplet abundance, there has recently been increasing interest in identifying key players in lipid droplet biology that suppress ferroptosis and whether these dependencies can be effectively exploited in cancer treatment. This article discusses how lipid droplet metabolism, including lipid synthesis, storage, and use modulates ferroptosis sensitivity or tolerance in different cancer models, focusing on glioblastoma.
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Affiliation(s)
- Ayenachew Bezawork-Geleta
- Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, Australia
| | - James Dimou
- Department of Surgery, The University of Melbourne, Parkville, VIC, Australia
- Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - Matthew J. Watt
- Department of Anatomy and Physiology, School of Biomedical Sciences, The University of Melbourne, Melbourne, VIC, Australia
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Day ZI, Mayfosh AJ, Giel MC, Hong Y, Williams SA, Santavanond JP, Rau TF, Poon IK, Hulett MD. Novel Formulation of Undecylenic Acid induces Tumor Cell Apoptosis. Int J Mol Sci 2022; 23:ijms232214170. [PMID: 36430646 PMCID: PMC9692760 DOI: 10.3390/ijms232214170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/28/2022] [Accepted: 11/10/2022] [Indexed: 11/18/2022] Open
Abstract
Undecylenic acid, a monounsaturated fatty acid, is currently in clinical use as a topical antifungal agent, however the potential for therapeutic application in other disease settings has not been investigated. In this study, we describe a novel platform for the solubilization of fatty acids using amino acids and utilize this approach to define a tumoricidal activity and underlying mechanism for undecylenic acid. We examined a novel formulation of undecylenic acid compounded with L-Arginine, called GS-1, that induced concentration-dependent tumor cell death, with undecylenic acid being the cytotoxic component. Further investigation revealed that GS-1-mediated cell death was caspase-dependent with a reduction in mitochondrial membrane potential, suggesting a pro-apoptotic mechanism of action. Additionally, GS-1 was found to localize intracellularly to lipid droplets. In contrast to previous studies where lipid droplets have been shown to be protective against fatty acid-induced cell death, we showed that lipid droplets could not protect against GS-1-induced cytotoxicity. We also found a role for Fatty Acid Transport Protein 2 (FATP2) in the uptake of this compound. Collectively, this study demonstrates that GS-1 has effective pro-apoptotic antitumor activity in vitro and, together with the novel platform of fatty acid solubilization, contributes to the re-emerging field of fatty acids as potential anti-cancer therapeutics.
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Affiliation(s)
- Zoe I. Day
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Alyce J. Mayfosh
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
- Wintermute Biomedical, 789 Bauer Lane, Corvallis, MT 59828, USA
| | - Marie-Claire Giel
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Yuning Hong
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Scott A. Williams
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Jascinta P. Santavanond
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Thomas F. Rau
- Wintermute Biomedical, 789 Bauer Lane, Corvallis, MT 59828, USA
| | - Ivan K. Poon
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
| | - Mark D. Hulett
- Department of Biochemistry and Chemistry, School of Agriculture, Biomedicine and Environment, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, Australia
- Correspondence: ; Tel.: +61-9479-1266
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10
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Beebe J, Josephraj S, Wang CJ, Danielson J, Cui Q, Huang C, Barlow L, Zhang RH, Zhang T, Nakshatri H, Dong Z, Li X, Liu JY, Zhang JT. Therapeutic Activity of the Lansoprazole Metabolite 5-Hydroxy Lansoprazole Sulfide in Triple-Negative Breast Cancer by Inhibiting the Enoyl Reductase of Fatty Acid Synthase. J Med Chem 2022; 65:13681-13691. [PMID: 36257066 DOI: 10.1021/acs.jmedchem.2c00642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Fatty acid synthase (FASN), a sole cytosolic enzyme responsible for de-novo lipid synthesis, is overexpressed in cancer but not in normal non-lipogenic tissues. FASN has been targeted, albeit no such inhibitor has been approved. Proton pump inhibitors (PPIs), approved for digestive disorders, were found to inhibit FASN with anticancer activities in attempting to repurpose Food and Drug Administration-approved drugs. Indeed, PPI usage benefited breast cancer patients and increased their response rate. Due to structural similarity, we thought that their metabolites might extend anticancer effects of PPIs by inhibiting FASN. Here, we tested this hypothesis and found that 5-hydroxy lansoprazole sulfide (5HLS), the end lansoprazole metabolite, was more active than lansoprazole in inhibiting FASN function and regulation of NHEJ repair of oxidative DNA damage via PARP1. Surprisingly, 5HLS inhibits the enoyl reductase, whereas lansoprazole inhibits the thioesterase of FASN. Thus, PPI metabolites may contribute to the lasting anticancer effects of PPIs by inhibiting FASN.
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Affiliation(s)
- Jenny Beebe
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Sophia Josephraj
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Chao J Wang
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Jacob Danielson
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Qingbin Cui
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Caoqinglong Huang
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Lincoln Barlow
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Ryan H Zhang
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Taolan Zhang
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Harikrishna Nakshatri
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Zizheng Dong
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Xiaohong Li
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Jing-Yuan Liu
- Department of Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
| | - Jian-Ting Zhang
- Department of Cell & Cancer Biology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio 43614, United States
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11
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Sun T, Liu D, Wu J, Lu WW, Zhao X, Wong TM, Liu ZL. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma. Open Med (Wars) 2022; 17:441-452. [PMID: 35350838 PMCID: PMC8919822 DOI: 10.1515/med-2022-0441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 12/29/2021] [Accepted: 01/24/2022] [Indexed: 11/15/2022] Open
Abstract
Osteosarcoma (OS) is the most common type of primary malignant bone tumor. The early lung metastasis of osteosarcoma is one of the main factors of poor prognosis. Therefore, searching for new targets and new mechanisms of osteosarcoma metastasis is essential for the prevention and treatment of osteosarcoma. Our previous studies suggested that fatty acid synthase (FASN) was an oncogene and promoted osteosarcoma. In addition, it is reported that the expression of miR-195 was negatively correlated with osteosarcoma. Aberrant DNA methylation can reversely regulate the expression of miRNAs. However, whether miR-195 could target FASN in osteosarcoma and whether ectopic DNA methylation is the upstream regulatory mechanism of miR-195 in metastasis of osteosarcoma are not fully studied. The expressions were detected by qPCR and western blot, and methylation level was determined by methylation-specific PCR. Luciferase reporter assay, MTT, wound healing, and Transwell assay were used. We found that the expression of miR-195 was low in osteosarcoma. The methylation of miR-195 was high. miR-195 targeted and decreased the expression of FASN. In osteosarcoma, miR-195 inhibited cell proliferation, cell migration, and invasion. The methylation of miR-195 was related to decreased miR-195, it might promote osteosarcoma.
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Affiliation(s)
- Tianhao Sun
- Shenzhen Key Laboratory for Innovative Technology in Ortho-paedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Dongning Liu
- Department of Spinal Surgery, Shenzhen Sixth People’s Hospital(Nanshan Hospital), Huazhong University of Science and Technology Union Shenzhen Hospital , Shenzhen , China
| | - Jun Wu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
| | - William W. Lu
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Xiaoli Zhao
- Research Center for Human Tissue and Organs Degeneration, Institute Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , China
| | - Tak Man Wong
- Shenzhen Key Laboratory for Innovative Technology in Orthopaedic Trauma, Guangdong Engineering Technology Research Center for Orthopaedic Trauma Repair, Department of Orthopaedics and Traumatology, The University of Hong Kong-Shenzhen Hospital , Shenzhen 518053 , China
| | - Zhi-Li Liu
- Institute of Spine and Spinal Cord, Department of Orthopedic Surgery, The First Affiliated Hospital of Nanchang University , Nanchang 330006 , China
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12
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Ma Y, Nenkov M, Chen Y, Press AT, Kaemmerer E, Gassler N. Fatty acid metabolism and acyl-CoA synthetases in the liver-gut axis. World J Hepatol 2021; 13:1512-1533. [PMID: 34904027 PMCID: PMC8637682 DOI: 10.4254/wjh.v13.i11.1512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/28/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
Fatty acids are energy substrates and cell components which participate in regulating signal transduction, transcription factor activity and secretion of bioactive lipid mediators. The acyl-CoA synthetases (ACSs) family containing 26 family members exhibits tissue-specific distribution, distinct fatty acid substrate preferences and diverse biological functions. Increasing evidence indicates that dysregulation of fatty acid metabolism in the liver-gut axis, designated as the bidirectional relationship between the gut, microbiome and liver, is closely associated with a range of human diseases including metabolic disorders, inflammatory disease and carcinoma in the gastrointestinal tract and liver. In this review, we depict the role of ACSs in fatty acid metabolism, possible molecular mechanisms through which they exert functions, and their involvement in hepatocellular and colorectal carcinoma, with particular attention paid to long-chain fatty acids and small-chain fatty acids. Additionally, the liver-gut communication and the liver and gut intersection with the microbiome as well as diseases related to microbiota imbalance in the liver-gut axis are addressed. Moreover, the development of potentially therapeutic small molecules, proteins and compounds targeting ACSs in cancer treatment is summarized.
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Affiliation(s)
- Yunxia Ma
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Miljana Nenkov
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Yuan Chen
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Adrian T Press
- Department of Anesthesiology and Intensive Care Medicine and Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Elke Kaemmerer
- Department of Pediatrics, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany
| | - Nikolaus Gassler
- Section Pathology, Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Jena 07747, Germany.
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13
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Huang J, Wang J, He H, Huang Z, Wu S, Chen C, Liu W, Xie L, Tao Y, Cong L, Jiang Y. Close interactions between lncRNAs, lipid metabolism and ferroptosis in cancer. Int J Biol Sci 2021; 17:4493-4513. [PMID: 34803512 PMCID: PMC8579446 DOI: 10.7150/ijbs.66181] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/01/2021] [Indexed: 12/19/2022] Open
Abstract
Abnormal lipid metabolism including synthesis, uptake, modification, degradation and transport has been considered a hallmark of malignant tumors and contributes to the supply of substances and energy for rapid cell growth. Meanwhile, abnormal lipid metabolism is also associated with lipid peroxidation, which plays an important role in a newly discovered type of regulated cell death termed ferroptosis. Long noncoding RNAs (lncRNAs) have been proven to be associated with the occurrence and progression of cancer. Growing evidence indicates that lncRNAs are key regulators of abnormal lipid metabolism and ferroptosis in cancer. In this review, we mainly summarized the mechanism by which lncRNAs regulate aberrant lipid metabolism in cancer, illustrated that lipid metabolism can also influence the expression of lncRNAs, and discussed the mechanism by which lncRNAs affect ferroptosis. A comprehensive understanding of the interactions between lncRNAs, lipid metabolism and ferroptosis could help us to develop novel strategies for precise cancer treatment in the future.
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Affiliation(s)
- Jingjing Huang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Jin Wang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Hua He
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Zichen Huang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Sufang Wu
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Chao Chen
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210013 Jiangsu, China
| | - Wenbing Liu
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Li Xie
- Department of Head and Neck Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, P.R. China
| | - Yongguang Tao
- Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Department of Pathology, Xiangya Hospital, School of Basic Medicine, Central South University, Changsha, 410078 Hunan, China
| | - Li Cong
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
| | - Yiqun Jiang
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha, 410013 Hunan, China.,School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China
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14
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Yang R, Ying G, Li B. Potential of electron transfer and its application in dictating routes of biochemical processes associated with metabolic reprogramming. Front Med 2021; 15:679-692. [PMID: 34302614 DOI: 10.1007/s11684-021-0866-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Accepted: 04/25/2021] [Indexed: 12/13/2022]
Abstract
Metabolic reprogramming, such as abnormal utilization of glucose, addiction to glutamine, and increased de-novo lipid synthesis, extensively occurs in proliferating cancer cells, but the underneath rationale has remained to be elucidated. Based on the concept of the degree of reduction of a compound, we have recently proposed a calculation termed as potential of electron transfer (PET), which is used to characterize the degree of electron redistribution coupled with metabolic transformations. When this calculation is combined with the assumed model of electron balance in a cellular context, the enforced selective reprogramming could be predicted by examining the net changes of the PET values associated with the biochemical pathways in anaerobic metabolism. Some interesting properties of PET in cancer cells were also discussed, and the model was extended to uncover the chemical nature underlying aerobic glycolysis that essentially results from energy requirement and electron balance. Enabling electron transfer could drive metabolic reprogramming in cancer metabolism. Therefore, the concept and model established on electron transfer could guide the treatment strategies of tumors and future studies on cellular metabolism.
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Affiliation(s)
- Ronghui Yang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Capital Medical University, Beijing, 100069, China
| | - Guoguang Ying
- Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
- Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, 300060, China.
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
| | - Binghui Li
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China.
- Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, 100069, China.
- Beijing Key Laboratory for Tumor Invasion and Metastasis, Capital Medical University, Beijing, 100069, China.
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15
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Li LY, Yang Q, Jiang YY, Yang W, Jiang Y, Li X, Hazawa M, Zhou B, Huang GW, Xu XE, Gery S, Zhang Y, Ding LW, Ho AS, Zumsteg ZS, Wang MR, Fullwood MJ, Freedland SJ, Meltzer SJ, Xu LY, Li EM, Koeffler HP, Lin DC. Interplay and cooperation between SREBF1 and master transcription factors regulate lipid metabolism and tumor-promoting pathways in squamous cancer. Nat Commun 2021; 12:4362. [PMID: 34272396 PMCID: PMC8285542 DOI: 10.1038/s41467-021-24656-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 06/29/2021] [Indexed: 02/05/2023] Open
Abstract
Squamous cell carcinomas (SCCs) comprise one of the most common histologic types of human cancer. Transcriptional dysregulation of SCC cells is orchestrated by tumor protein p63 (TP63), a master transcription factor (TF) and a well-researched SCC-specific oncogene. In the present study, both Gene Set Enrichment Analysis (GSEA) of SCC patient samples and in vitro loss-of-function assays establish fatty-acid metabolism as a key pathway downstream of TP63. Further studies identify sterol regulatory element binding transcription factor 1 (SREBF1) as a central mediator linking TP63 with fatty-acid metabolism, which regulates the biosynthesis of fatty-acids, sphingolipids (SL), and glycerophospholipids (GPL), as revealed by liquid chromatography tandem mass spectrometry (LC-MS/MS)-based lipidomics. Moreover, a feedback co-regulatory loop consisting of SREBF1/TP63/Kruppel like factor 5 (KLF5) is identified, which promotes overexpression of all three TFs in SCCs. Downstream of SREBF1, a non-canonical, SCC-specific function is elucidated: SREBF1 cooperates with TP63/KLF5 to regulate hundreds of cis-regulatory elements across the SCC epigenome, which converge on activating cancer-promoting pathways. Indeed, SREBF1 is essential for SCC viability and migration, and its overexpression is associated with poor survival in SCC patients. Taken together, these data shed light on mechanisms of transcriptional dysregulation in cancer, identify specific epigenetic regulators of lipid metabolism, and uncover SREBF1 as a potential therapeutic target and prognostic marker in SCC.
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Affiliation(s)
- Li-Yan Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
| | - Qian Yang
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yan-Yi Jiang
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Wei Yang
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Yuan Jiang
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiang Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Masaharu Hazawa
- Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Japan
| | - Bo Zhou
- Departments of Surgery and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Guo-Wei Huang
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Xiu-E Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China
| | - Sigal Gery
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ying Zhang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Ling-Wen Ding
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Allen S Ho
- Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Zachary S Zumsteg
- Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Ming-Rong Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Melissa J Fullwood
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Stephen J Freedland
- Division of Urology, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, USA and the Durham VA Medical Center, Durham, NC, USA
| | - Stephen J Meltzer
- Departments of Medicine and Oncology, Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Li-Yan Xu
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
| | - En-Min Li
- The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
| | - H Phillip Koeffler
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - De-Chen Lin
- Department of Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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16
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Yuan ZH, Liu T, Wang H, Xue LX, Wang JJ. Fatty Acids Metabolism: The Bridge Between Ferroptosis and Ionizing Radiation. Front Cell Dev Biol 2021; 9:675617. [PMID: 34249928 PMCID: PMC8264768 DOI: 10.3389/fcell.2021.675617] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/04/2021] [Indexed: 12/14/2022] Open
Abstract
Exposure of tumor cells to ionizing radiation (IR) alters the microenvironment, particularly the fatty acid (FA) profile and activity. Moreover, abnormal FA metabolism, either catabolism or anabolism, is essential for synthesizing biological membranes and delivering molecular signals to induce ferroptotic cell death. The current review focuses on the bistable regulation characteristics of FA metabolism and explains how FA catabolism and anabolism pathway crosstalk harmonize different ionizing radiation-regulated ferroptosis responses, resulting in pivotal cell fate decisions. In summary, targeting key molecules involved in lipid metabolism and ferroptosis may amplify the tumor response to IR.
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Affiliation(s)
- Zhu-hui Yuan
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Tong Liu
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
| | - Hao Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
| | - Li-xiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China
- Biobank, Peking University Third Hospital, Beijing, China
| | - Jun-jie Wang
- Department of Radiation Oncology, Peking University Third Hospital, Beijing, China
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17
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Paiva P, Medina FE, Viegas M, Ferreira P, Neves RPP, Sousa JPM, Ramos MJ, Fernandes PA. Animal Fatty Acid Synthase: A Chemical Nanofactory. Chem Rev 2021; 121:9502-9553. [PMID: 34156235 DOI: 10.1021/acs.chemrev.1c00147] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Fatty acids are crucial molecules for most living beings, very well spread and conserved across species. These molecules play a role in energy storage, cell membrane architecture, and cell signaling, the latter through their derivative metabolites. De novo synthesis of fatty acids is a complex chemical process that can be achieved either by a metabolic pathway built by a sequence of individual enzymes, such as in most bacteria, or by a single, large multi-enzyme, which incorporates all the chemical capabilities of the metabolic pathway, such as in animals and fungi, and in some bacteria. Here we focus on the multi-enzymes, specifically in the animal fatty acid synthase (FAS). We start by providing a historical overview of this vast field of research. We follow by describing the extraordinary architecture of animal FAS, a homodimeric multi-enzyme with seven different active sites per dimer, including a carrier protein that carries the intermediates from one active site to the next. We then delve into this multi-enzyme's detailed chemistry and critically discuss the current knowledge on the chemical mechanism of each of the steps necessary to synthesize a single fatty acid molecule with atomic detail. In line with this, we discuss the potential and achieved FAS applications in biotechnology, as biosynthetic machines, and compare them with their homologous polyketide synthases, which are also finding wide applications in the same field. Finally, we discuss some open questions on the architecture of FAS, such as their peculiar substrate-shuttling arm, and describe possible reasons for the emergence of large megasynthases during evolution, questions that have fascinated biochemists from long ago but are still far from answered and understood.
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Affiliation(s)
- Pedro Paiva
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Fabiola E Medina
- Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Autopista Concepción-Talcahuano, 7100 Talcahuano, Chile
| | - Matilde Viegas
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Pedro Ferreira
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Rui P P Neves
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - João P M Sousa
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Maria J Ramos
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
| | - Pedro A Fernandes
- LAQV, REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal
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18
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Ingram LM, Finnerty MC, Mansoura M, Chou CW, Cummings BS. Identification of lipidomic profiles associated with drug-resistant prostate cancer cells. Lipids Health Dis 2021; 20:15. [PMID: 33596934 PMCID: PMC7890620 DOI: 10.1186/s12944-021-01437-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Accepted: 01/26/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The association of circulating lipids with clinical outcomes of drug-resistant castration-resistant prostate cancer (DR-CRPC) is not fully understood. While it is known that increases in select lipids correlate to decreased survival, neither the mechanisms mediating these alterations nor the correlation of resistance to drug treatments is well characterized. METHODS This gap-in-knowledge was addressed using in vitro models of non-cancerous, hormone-sensitive, CRPC and drug-resistant cell lines combined with quantitative LC-ESI-Orbitrap-MS (LC-ESI-MS/MS) lipidomic analysis and subsequent analysis such as Metaboanalyst and Lipid Pathway Enrichment Analysis (LIPEA). RESULTS Several lipid regulatory pathways were identified that are associated with Docetaxel resistance in prostate cancer (PCa). These included those controlling glycerophospholipid metabolism, sphingolipid signaling and ferroptosis. In total, 7460 features were identified as being dysregulated between the cell lines studied, and 21 lipid species were significantly altered in drug-resistant cell lines as compared to nonresistant cell lines. Docetaxel resistance cells (PC3-Rx and DU145-DR) had higher levels of phosphatidylcholine (PC), oxidized lipid species, phosphatidylethanolamine (PE), and sphingomyelin (SM) as compared to parent control cells (PC-3 and DU-145). Alterations were also identified in the levels of phosphatidic acid (PA) and diacylglyceride (DAG), whose levels are regulated by Lipin (LPIN), a phosphatidic acid phosphatase that converts PA to DAG. Data derived from cBioPortal demonstrated a population of PCa patients expressing mutations aligning with amplification of LPIN1, LPIN2 and LPIN3 genes. Lipin amplification in these genes correlated to decreased survival in these patients. Lipin-1 mRNA expression also showed a similar trend in PCa patient data. Lipin-1, but not Lipin-2 or - 3, was detected in several prostate cancer cells, and was increased in 22RV1 and PC-3 cell lines. The increased expression of Lipin-1 in these cells correlated with the level of PA. CONCLUSION These data identify lipids whose levels may correlate to Docetaxel sensitivity and progression of PCa. The data also suggest a correlation between the expression of Lipin-1 in cells and patients with regards to prostate cancer cell aggressiveness and patient survivability. Ultimately, these data may be useful for identifying markers of lethal and/or metastatic prostate cancer.
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Affiliation(s)
- Lishann M Ingram
- Pharmaceutical and Biomedical Sciences, 450 College of Pharmacy South, University of Georgia, Athens, GA, 30602, USA
| | - Morgan C Finnerty
- Pharmaceutical and Biomedical Sciences, 450 College of Pharmacy South, University of Georgia, Athens, GA, 30602, USA
| | - Maryam Mansoura
- Pharmaceutical and Biomedical Sciences, 450 College of Pharmacy South, University of Georgia, Athens, GA, 30602, USA
| | - Chau-Wen Chou
- Proteomics and Mass Spectrometry Facility (PAMS), Department of Chemistry, University of Georgia, Athens, GA, USA
| | - Brian S Cummings
- Pharmaceutical and Biomedical Sciences, 450 College of Pharmacy South, University of Georgia, Athens, GA, 30602, USA.
- Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA.
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19
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Abstract
The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is clinical and experimental evidence that an increased fructose intake promotes cancer growth. The precise mechanism, however, in which fructose induces tumor growth is still not fully understood. In this article, we present an overview of the metabolic pathways that utilize fructose and how fructose metabolism can sustain cancer cell proliferation. Although the degradation of fructose shares many of the enzymes and metabolic intermediates with glucose metabolism through glycolysis, glucose and fructose are metabolized differently. We describe the different metabolic fates of fructose carbons and how they are connected to lipogenesis and nucleotide synthesis. In addition, we discuss how the endogenous production of fructose from glucose via the polyol pathway can be beneficial for cancer cells.
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20
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Abstract
Heparanase is the only mammalian enzyme that cleaves heparan sulphate, an important component of the extracellular matrix. This leads to the remodelling of the extracellular matrix, whilst liberating growth factors and cytokines bound to heparan sulphate. This in turn promotes both physiological and pathological processes such as angiogenesis, immune cell migration, inflammation, wound healing and metastasis. Furthermore, heparanase exhibits non-enzymatic actions in cell signalling and in regulating gene expression. Cancer is underpinned by key characteristic features that promote malignant growth and disease progression, collectively termed the 'hallmarks of cancer'. Essentially, all cancers examined to date have been reported to overexpress heparanase, leading to enhanced tumour growth and metastasis with concomitant poor patient survival. With its multiple roles within the tumour microenvironment, heparanase has been demonstrated to regulate each of these hallmark features, in turn highlighting the need for heparanase-targeted therapies. However, recent discoveries which demonstrated that heparanase can also regulate vital anti-tumour mechanisms have cast doubt on this approach. This review will explore the myriad ways by which heparanase functions as a key regulator of the hallmarks of cancer and will highlight its role as a major component within the tumour microenvironment. The dual role of heparanase within the tumour microenvironment, however, emphasises the need for further investigation into defining its precise mechanism of action in different cancer settings.
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Affiliation(s)
- Krishnath M Jayatilleke
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Plenty Road & Kingsbury Drive, Melbourne, VIC, 3086, Australia
| | - Mark D Hulett
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Plenty Road & Kingsbury Drive, Melbourne, VIC, 3086, Australia.
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21
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Cruz-Gil S, Fernández LP, Sánchez-Martínez R, Gómez de Cedrón M, Ramírez de Molina A. Non-Coding and Regulatory RNAs as Epigenetic Remodelers of Fatty Acid Homeostasis in Cancer. Cancers (Basel) 2020; 12:E2890. [PMID: 33050166 PMCID: PMC7599548 DOI: 10.3390/cancers12102890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 10/05/2020] [Accepted: 10/07/2020] [Indexed: 02/06/2023] Open
Abstract
Cancer cells commonly display metabolic fluctuations. Together with the Warburg effect and the increased glutaminolysis, alterations in lipid metabolism homeostasis have been recognized as a hallmark of cancer. Highly proliferative cancer cells upregulate de novo synthesis of fatty acids (FAs) which are required to support tumor progression by exerting multiple roles including structural cell membrane composition, regulators of the intracellular redox homeostasis, ATP synthesis, intracellular cell signaling molecules, and extracellular mediators of the tumor microenvironment. Epigenetic modifications have been shown to play a crucial role in human development, but also in the initiation and progression of complex diseases. The study of epigenetic processes could help to design new integral strategies for the prevention and treatment of metabolic disorders including cancer. Herein, we first describe the main altered intracellular fatty acid processes to support cancer initiation and progression. Next, we focus on the most important regulatory and non-coding RNAs (small noncoding RNA-sncRNAs-long non-coding RNAs-lncRNAs-and other regulatory RNAs) which may target the altered fatty acids pathway in cancer.
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Affiliation(s)
| | | | | | - Marta Gómez de Cedrón
- Correspondence: (M.G.d.C.); (A.R.d.M.); Tel.: +34-67-213-49-21 (A.R.d.M.); Fax: +34-91-830-59-61 (A.R.d.M.)
| | - Ana Ramírez de Molina
- Laboratory of Molecular Oncology, IMDEA-Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain; (S.C.-G.); (L.P.F.); (R.S.-M.)
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22
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Turdo A, Porcelli G, D’Accardo C, Di Franco S, Verona F, Forte S, Giuffrida D, Memeo L, Todaro M, Stassi G. Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities. Cancers (Basel) 2020; 12:E1436. [PMID: 32486505 PMCID: PMC7352619 DOI: 10.3390/cancers12061436] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/27/2020] [Accepted: 05/30/2020] [Indexed: 02/07/2023] Open
Abstract
Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells-termed cancer stem cells (CSCs)-which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.
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Affiliation(s)
- Alice Turdo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Gaetana Porcelli
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Caterina D’Accardo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Simone Di Franco
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Francesco Verona
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
| | - Stefano Forte
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Dario Giuffrida
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology (IOM), 95029 Catania, Italy; (S.F.); (D.G.); (L.M.)
| | - Matilde Todaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, 90127 Palermo, Italy; (A.T.); (C.D.); (M.T.)
| | - Giorgio Stassi
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy; (G.P.); (S.D.F.); (F.V.)
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23
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Feng WW, Kurokawa M. Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3. [PMID: 32226926 PMCID: PMC7100881 DOI: 10.20517/cdr.2019.100] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.
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Affiliation(s)
- William W Feng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Manabu Kurokawa
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
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24
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Fakhri S, Moradi SZ, Farzaei MH, Bishayee A. Modulation of dysregulated cancer metabolism by plant secondary metabolites: A mechanistic review. Semin Cancer Biol 2020; 80:276-305. [PMID: 32081639 DOI: 10.1016/j.semcancer.2020.02.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 12/12/2022]
Abstract
Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe natural compounds has been a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment.
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Affiliation(s)
- Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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25
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Feng WW, Wilkins O, Bang S, Ung M, Li J, An J, Del Genio C, Canfield K, DiRenzo J, Wells W, Gaur A, Robey RB, Guo JY, Powles RL, Sotiriou C, Pusztai L, Febbraio M, Cheng C, Kinlaw WB, Kurokawa M. CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies. Cell Rep 2019; 29:3405-3420.e5. [PMID: 31825825 PMCID: PMC6938262 DOI: 10.1016/j.celrep.2019.11.008] [Citation(s) in RCA: 132] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 08/22/2019] [Accepted: 11/04/2019] [Indexed: 11/18/2022] Open
Abstract
Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTV-neu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.
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Affiliation(s)
- William W Feng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Owen Wilkins
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Scott Bang
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Matthew Ung
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Jiaqi Li
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Jennifer An
- Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
| | - Carmen Del Genio
- Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
| | - Kaleigh Canfield
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - James DiRenzo
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Wendy Wells
- Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA
| | - Arti Gaur
- Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA
| | - R Brooks Robey
- Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Medical Education, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; White River Junction Veterans Affairs Medical Center, White River Junction, VT 05009, USA
| | | | - Ryan L Powles
- Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 05620, USA
| | - Christos Sotiriou
- Breast Cancer Translational Research Laboratory J.-C. Heuson, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Lajos Pusztai
- Breast Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 05620, USA
| | - Maria Febbraio
- Department of Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Chao Cheng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA; Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - William B Kinlaw
- Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA
| | - Manabu Kurokawa
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Department of Biological Sciences, Kent State University, Kent, OH 44242, USA.
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26
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Chen M, Huang J. The expanded role of fatty acid metabolism in cancer: new aspects and targets. PRECISION CLINICAL MEDICINE 2019; 2:183-191. [PMID: 31598388 PMCID: PMC6770278 DOI: 10.1093/pcmedi/pbz017] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/19/2019] [Accepted: 08/19/2019] [Indexed: 12/24/2022] Open
Abstract
Cancer cells undergo metabolic reprogramming to support cell proliferation, growth, and
dissemination. Alterations in lipid metabolism, and specifically the uptake and synthesis
of fatty acids (FAs), comprise one well-documented aspect of this reprogramming. Recent
studies have revealed an expanded range of roles played by FA in promoting the
aggressiveness of cancer while simultaneously identifying new potential targets for cancer
therapy. This article provides a brief review of these advances in our understanding of FA
metabolism in cancer, highlighting both recent discoveries and the inherent challenges
caused by the metabolic plasticity of cancer cells in targeting lipid metabolism for
cancer therapy.
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Affiliation(s)
- Ming Chen
- Department of Pathology, Duke University School of Medicine, Duke Cancer Institute, Duke University, Durham, NC 27514, USA
| | - Jiaoti Huang
- Department of Pathology, Duke University School of Medicine, Duke Cancer Institute, Duke University, Durham, NC 27514, USA
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27
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Gimple RC, Kidwell RL, Kim LJY, Sun T, Gromovsky AD, Wu Q, Wolf M, Lv D, Bhargava S, Jiang L, Prager BC, Wang X, Ye Q, Zhu Z, Zhang G, Dong Z, Zhao L, Lee D, Bi J, Sloan AE, Mischel PS, Brown JM, Cang H, Huan T, Mack SC, Xie Q, Rich JN. Glioma Stem Cell-Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling. Cancer Discov 2019; 9:1248-1267. [PMID: 31201181 DOI: 10.1158/2159-8290.cd-19-0061] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 05/03/2019] [Accepted: 06/11/2019] [Indexed: 01/02/2023]
Abstract
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs. SIGNIFICANCE: Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state-specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.See related commentary by Affronti and Wellen, p. 1161.This article is highlighted in the In This Issue feature, p. 1143.
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Affiliation(s)
- Ryan C Gimple
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.,Department of Pathology, Case Western University, Cleveland, Ohio
| | - Reilly L Kidwell
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Leo J Y Kim
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.,Department of Pathology, Case Western University, Cleveland, Ohio
| | - Tengqian Sun
- Salk Institute for Biological Studies, La Jolla, California
| | - Anthony D Gromovsky
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio
| | - Qiulian Wu
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Megan Wolf
- Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Deguan Lv
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Shruti Bhargava
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Li Jiang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Briana C Prager
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California.,Department of Pathology, Case Western University, Cleveland, Ohio.,Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio
| | - Xiuxing Wang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Qing Ye
- Salk Institute for Biological Studies, La Jolla, California
| | - Zhe Zhu
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Guoxin Zhang
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Zhen Dong
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Linjie Zhao
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Derrick Lee
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California
| | - Junfeng Bi
- Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California
| | - Andrew E Sloan
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland Ohio.,Department of Neurological Surgery, University Hospitals-Cleveland Medical Center, Cleveland, Ohio
| | - Paul S Mischel
- Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, California.,Department of Pathology, UCSD School of Medicine, La Jolla, California.,Moores Cancer Center, UCSD School of Medicine, La Jolla, California
| | - J Mark Brown
- Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio
| | - Hu Cang
- Salk Institute for Biological Studies, La Jolla, California
| | - Tao Huan
- Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada
| | - Stephen C Mack
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas.,Dan L. Duncan Cancer Center, Houston, Texas
| | - Qi Xie
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California. .,Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Westlake University, Hangzhou, China
| | - Jeremy N Rich
- Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, San Diego, California. .,Moores Cancer Center, UCSD School of Medicine, La Jolla, California.,Department of Neurosciences, UCSD School of Medicine, La Jolla, California
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28
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Jagust P, de Luxán-Delgado B, Parejo-Alonso B, Sancho P. Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells. Front Pharmacol 2019; 10:203. [PMID: 30967773 PMCID: PMC6438930 DOI: 10.3389/fphar.2019.00203] [Citation(s) in RCA: 90] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 02/18/2019] [Indexed: 02/02/2023] Open
Abstract
Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.
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Affiliation(s)
- Petra Jagust
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz de Luxán-Delgado
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Beatriz Parejo-Alonso
- Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
| | - Patricia Sancho
- Centre for Stem Cells in Cancer and Ageing, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.,Traslational Research Unit, Hospital Universitario Miguel Servet, Aragon Institute for Health Research (IIS Aragon), Zaragoza, Spain
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29
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Zhou L, Wang Z, Hu C, Zhang C, Kovatcheva-Datchary P, Yu D, Liu S, Ren F, Wang X, Li Y, Hou X, Piao H, Lu X, Zhang Y, Xu G. Integrated Metabolomics and Lipidomics Analyses Reveal Metabolic Reprogramming in Human Glioma with IDH1 Mutation. J Proteome Res 2019; 18:960-969. [PMID: 30596429 DOI: 10.1021/acs.jproteome.8b00663] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Mutations in isocitrate dehydrogenase ( IDH) 1 are high-frequency events in low-grade glioma and secondary glioblastoma, and IDH1 mutant gliomas are vulnerable to interventions. Metabolic reprogramming is a hallmark of cancer. In this study, comprehensive metabolism investigation of clinical IDH1 mutant glioma specimens was performed to explore its specific metabolic reprogramming in real microenvironment. Massive metabolic alterations from glycolysis to lipid metabolism were identified in the IDH1 mutant glioma tissue when compared to IDH1 wild-type glioma. Of note, tricarboxylic acid (TCA) cycle intermediates were in similar levels in both groups, with more pyruvate found entering the TCA cycle in IDH1 mutant glioma. The pool of fatty acyl chains was also reduced, displayed as decreased triglycerides and sphingolipids, although membrane phosphatidyl lipids were not changed. The lower fatty acyl pool may be mediated by the lower protein expression levels of long-chain acyl-CoA synthetase 1 (ACSL1), ACSL4, and very long-chain acyl-CoA synthetase 3 (ACSVL3) in IDH1 mutant glioma. Lower ACSL1 was further found to contribute to the better survival of IDH1 mutant glioma patients based on the The Cancer Genome Atlas (TCGA) RNA sequencing data. Our research provides valuable insights into the tissue metabolism of human IDH1 mutant glioma and unravels new lipid-related targets.
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Affiliation(s)
- Lina Zhou
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Zhichao Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
- University of Chinese Academy of Sciences , Beijing 100049 , P. R. China
| | - Chunxiu Hu
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Chaoqi Zhang
- Biotherapy Center and Cancer Center , The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 , P. R. China
| | - Petia Kovatcheva-Datchary
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Di Yu
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
- University of Chinese Academy of Sciences , Beijing 100049 , P. R. China
| | - Shasha Liu
- Biotherapy Center and Cancer Center , The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 , P. R. China
| | - Feifei Ren
- Biotherapy Center and Cancer Center , The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 , P. R. China
| | - Xiaolin Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Yanli Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Xiaoli Hou
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Hailong Piao
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Xin Lu
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
| | - Yi Zhang
- Biotherapy Center and Cancer Center , The First Affiliated Hospital of Zhengzhou University , Zhengzhou 450052 , P. R. China
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian 116023 , P. R. China
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30
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Lin C, Salzillo TC, Bader DA, Wilkenfeld SR, Awad D, Pulliam TL, Dutta P, Pudakalakatti S, Titus M, McGuire SE, Bhattacharya PK, Frigo DE. Prostate Cancer Energetics and Biosynthesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1210:185-237. [PMID: 31900911 PMCID: PMC8096614 DOI: 10.1007/978-3-030-32656-2_10] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.
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Affiliation(s)
- Chenchu Lin
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Travis C Salzillo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - David A Bader
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Sandi R Wilkenfeld
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Dominik Awad
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Thomas L Pulliam
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Prasanta Dutta
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shivanand Pudakalakatti
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Titus
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sean E McGuire
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pratip K Bhattacharya
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Daniel E Frigo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Molecular Medicine Program, The Houston Methodist Research Institute, Houston, TX, USA.
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Khalid A, Siddiqui AJ, Huang JH, Shamsi T, Musharraf SG. Alteration of Serum Free Fatty Acids are Indicators for Progression of Pre-leukaemia Diseases to Leukaemia. Sci Rep 2018; 8:14883. [PMID: 30291286 PMCID: PMC6173776 DOI: 10.1038/s41598-018-33224-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 09/05/2018] [Indexed: 02/08/2023] Open
Abstract
Acute Leukaemia (AL) is a neoplasm of WBCs (white blood cells). Being an important class of metabolites, alteration in free fatty acids (FFAs) levels play a key role in cancer development and progression. As they involve in cell signaling, maintain membrane integrity, regulate homeostasis and effect cell and tissue functions. Considering this fact, a comprehensive analysis of FFAs was conducted to monitor their alteration in AL, pre-leukaemic diseases and healthy control. Fifteen FFAs were analyzed in 179 serum samples of myelodysplastic syndrome (MDS), aplastic anemia (APA), acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML) and healthy control using gas chromatography-multiple reaction monitoring-mass spectrometry (GC-MRM-MS). A multivariate statistical method of random forest (RF) was employed for chemometric analysis. Serum level of two FFAs including C18:0 and C14:0 were found discriminative among all five groups, and between ALL and AML, respectively. Moreover, C14:0 was identified as differentiated FFAs for systematic progression of pre-leukaemic conditions towards AML. C16:0 came as discriminated FFAs between APA and MDS/AML. Over all it was identified that FFAs profile not only become altered in leukaemia but also in pre-leukaemic diseases.
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Affiliation(s)
- Ayesha Khalid
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Amna Jabbar Siddiqui
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Jian-Hua Huang
- TCM and Ethnomedicine Innovation and Development Laboratory, Changsha, Hunan, China
| | - Tahir Shamsi
- National Institute of Blood Diseases and Bone Marrow Transplantation, Karachi, Pakistan
| | - Syed Ghulam Musharraf
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Role of RNF20 in cancer development and progression - a comprehensive review. Biosci Rep 2018; 38:BSR20171287. [PMID: 29934362 PMCID: PMC6043722 DOI: 10.1042/bsr20171287] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 06/20/2018] [Accepted: 06/22/2018] [Indexed: 02/06/2023] Open
Abstract
Evolving strategies to counter cancer initiation and progression rely on the identification of novel therapeutic targets that exploit the aberrant genetic changes driving oncogenesis. Several chromatin associated enzymes have been shown to influence post-translational modification (PTM) in DNA, histones, and non-histone proteins. Any deregulation of this core group of enzymes often leads to cancer development. Ubiquitylation of histone H2B in mammalian cells was identified over three decades ago. An exciting really interesting new gene (RING) family of E3 ubiquitin ligases, known as RNF20 and RNF40, monoubiquitinates histone H2A at K119 or H2B at K120, is known to function in transcriptional elongation, DNA double-strand break (DSB) repair processes, maintenance of chromatin differentiation, and exerting tumor suppressor activity. RNF20 is somatically altered in breast, lung, prostate cancer, clear cell renal cell carcinoma (ccRCC), and mixed lineage leukemia, and its reduced expression is a key factor in initiating genome instability; and it also functions as one of the significant driving factors of oncogenesis. Loss of RNF20/40 and H2B monoubiquitination (H2Bub1) is found in several cancers and is linked to an aggressive phenotype, and is also an indicator of poor prognosis. In this review, we summarized the current knowledge of RNF20 in chronic inflammation-driven cancers, DNA DSBs, and apoptosis, and its impact on chromatin structure beyond the single nucleosome level.
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Abstract
Cancer stem cells are a subpopulation of cells within a tumour believed to confer resistance to standard cancer therapies. Although many studies have addressed the specific mechanisms of tumour recurrence driven by cancer stem cells, cellular metabolism is an often-neglected attribute. The metabolic features of cancer stem cells are still poorly understood, and they thus constitute a promising field in cancer research. The findings published so far point to a distinct metabolic phenotype in cancer stem cells, which might depend on the cancer type, the model system used or even the experimental design, and several controversies still need to be tackled. This Review describes the metabolic phenotype of cancer stem cells by addressing the main metabolic traits in different tumours, including glycolysis and oxidative, glutamine, fatty acid and amino acid metabolism. In the context of these pathways, we also mention the specific alterations in metabolic enzymes and metabolite levels that have a role in the regulation of cancer stemness. Determining the role of metabolism in supporting resistance to therapy driven by cancer stem cells can raise the opportunity for novel therapeutic targets, which might not only eliminate this resistant population, but, more importantly, eradicate the whole tumour in a relapse-free scenario. Summary: The intrinsic mechanisms that define cancer stem cells, specifically their metabolic properties, are summarized in this Review, in an attempt to point out the benefit of targeting metabolism as a novel therapeutic approach.
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Affiliation(s)
- Joana Peixoto
- Cancer Signalling and Metabolism Group, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal.,Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-465 Porto, Portugal.,Medical Faculty of the University of Porto, 4200-319 Porto, Portugal.,Department of Biochemistry and Molecular Biology, Theodor-Boveri-Institute, Biocenter, 97074 Würzburg, Germany
| | - Jorge Lima
- Cancer Signalling and Metabolism Group, Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal .,Cancer Signalling and Metabolism Group, Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-465 Porto, Portugal.,Medical Faculty of the University of Porto, 4200-319 Porto, Portugal
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34
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Counihan JL, Grossman EA, Nomura DK. Cancer Metabolism: Current Understanding and Therapies. Chem Rev 2018; 118:6893-6923. [DOI: 10.1021/acs.chemrev.7b00775] [Citation(s) in RCA: 113] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Jessica L. Counihan
- Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States
| | - Elizabeth A. Grossman
- Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States
| | - Daniel K. Nomura
- Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States
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35
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Fuentes NR, Kim E, Fan YY, Chapkin RS. Omega-3 fatty acids, membrane remodeling and cancer prevention. Mol Aspects Med 2018; 64:79-91. [PMID: 29627343 DOI: 10.1016/j.mam.2018.04.001] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 03/27/2018] [Accepted: 04/04/2018] [Indexed: 12/20/2022]
Abstract
Proteins are often credited as the macromolecule responsible for performing critical cellular functions, however lipids have recently garnered more attention as our understanding of their role in cell function and human health becomes more apparent. Although cellular membranes are the lipid environment in which many proteins function, it is now apparent that protein and lipid assemblies can be organized to form distinct micro- or nanodomains that facilitate signaling events. Indeed, it is now appreciated that cellular function is partly regulated by the specific spatiotemporal lipid composition of the membrane, down to the nanosecond and nanometer scale. Furthermore, membrane composition is altered during human disease processes such as cancer and obesity. For example, an increased rate of lipid/cholesterol synthesis in cancerous tissues has long been recognized as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids/cholesterol to cellular function in disease models is not yet fully understood. Furthermore, an important consideration in regard to human health is that diet is a major modulator of cell membrane composition. This can occur directly through incorporation of membrane substrates, such as fatty acids, e.g., n-3 polyunsaturated fatty acids (n-3 PUFA) and cholesterol. In this review, we describe scenarios in which changes in membrane composition impact human health. Particular focus is placed on the importance of intrinsic lipid/cholesterol biosynthesis and metabolism and extrinsic dietary modification in cancer and its effect on plasma membrane properties.
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Affiliation(s)
- Natividad R Fuentes
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Faculty of Toxicology, Texas A&M University, USA
| | - Eunjoo Kim
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Department of Molecular and Cellular Medicine, Texas A&M University, USA
| | - Yang-Yi Fan
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Department of Nutrition & Food Science, Texas A&M University, USA
| | - Robert S Chapkin
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, USA; Faculty of Toxicology, Texas A&M University, USA; Department of Nutrition & Food Science, Texas A&M University, USA; Center for Translational Environmental Health Research, Texas A&M University, USA.
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Saab J, Santos-Zabala ML, Loda M, Stack EC, Hollmann TJ. Fatty Acid Synthase and Acetyl-CoA Carboxylase Are Expressed in Nodal Metastatic Melanoma But Not in Benign Intracapsular Nodal Nevi. Am J Dermatopathol 2018; 40:259-264. [PMID: 28654463 PMCID: PMC6844149 DOI: 10.1097/dad.0000000000000939] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND Melanoma is a potentially lethal form of skin cancer for which the current standard therapy is complete surgical removal of the primary tumor followed by sentinel lymph node biopsy when indicated. Histologic identification of metastatic melanoma in a sentinel node has significant prognostic and therapeutic implications, routinely guiding further surgical management with regional lymphadenectomy. While melanocytes in a lymph node can be identified by routine histopathologic and immunohistochemical examination, the distinction between nodal nevus cells and melanoma can be morphologically problematic. Previous studies have shown that malignant melanoma can over-express metabolic genes such as fatty acid synthase (FASN) and acetyl-CoA carboxylase (ACC). This immunohistochemical study aims to compare the utility of FASN and ACC in differentiating sentinel lymph nodes with metastatic melanomas from those with benign nodal nevi in patients with cutaneous melanoma. MATERIALS AND METHODS Using antibodies against FASN and ACC, 13 sentinel lymph nodes from 13 patients with metastatic melanoma and 14 lymph nodes harboring benign intracapsular nevi from 14 patients with cutaneous malignant melanoma were examined. A diagnosis of nodal melanoma was based on cytologic atypia and histologic comparison with the primary melanoma. All nodal nevi were intracapsular and not trabecular. Immunohistochemistry for Melan-A, S100, human melanoma black 45 (HMB45), FASN, and ACC were performed. The percentage of melanocytes staining with HMB45, FASN, and ACC was determined and graded in 25% increments; staining intensity was graded as weak, moderate, or strong. RESULTS All metastatic melanomas tested had at least 25% tumor cell staining for both FASN and ACC. Greater than 75% of the tumor cells stained with FAS in 7/13 cases and for ACC in 5/12 cases. Intensity of staining was variable; strong staining for FASN and ACC was observed in 69% and 50% of metastatic melanoma, respectively. HMB45 was negative in 40% of nodal melanoma cases all of which stained with FASN and ACC. Capsular nevi were uniformly negative for FASN, ACC, and HMB45 immunoreactivity. CONCLUSIONS All metastatic melanoma cases involving sentinel lymph nodes were positive for FASN and ACC while no staining was observed in intracapsular nevi. These findings suggest that FASN and ACC could be used as valuable ancillary stains in the distinction between nodal nevi and metastatic melanoma.
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Affiliation(s)
- Jad Saab
- Memorial Sloan Kettering Cancer Center, New York, NY
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Huang LH, Chung HY, Su HM. Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line. BMC Cancer 2017; 17:890. [PMID: 29282029 PMCID: PMC5745739 DOI: 10.1186/s12885-017-3936-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 12/19/2017] [Indexed: 12/02/2022] Open
Abstract
Background Fatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver. We previously found a positive association between rat mammary tumor levels of the n-6 PUFA arachidonic acid (AA) and tumor weight. We examined the roles of the major n-3 PUFA, docosahexaenoic acid (DHA, 22:6n-3), and the major n-6 PUFA, AA, in FASN expression in, and proliferation of, human breast cancer MCF-7 cells. Methods The cells were treated for 48 h with BSA or 60 μM BSA-bound DHA, AA, or oleic acid (OA, 18:1n-9), then were incubated with or without estradiol or insulin. Western blot and 3H–thymidine incorporation assay were used to determine the role of DHA on FASN regulation and MCF-7 cell proliferation. Results DHA, but neither AA nor OA, inhibits estradiol-induced and insulin-induced expression of the precursor of sterol regulatory element binding protein-1 (p-SREBP-1), its mature form (m-SREBP-1), and FASN. Estradiol or insulin stimulation increased the pAkt/Akt and pS6/S6 ratios, expression of p-SREBP-1, m-SREBP-1, and FASN, and cell proliferation, and these effects were decreased by DHA. The DHA-induced decrease in FASN expression resulted from reduced pAkt/Akt signaling and not pERK1/2/ERK1/2 signaling. In addition, DHA enhanced the inhibitory effect of LY294002 on pAkt signaling and expression of p-SREBP-1, m-SREBP-1, and FASN. However, addition of rapamycin, an inhibitor of the mTOR signaling pathways, 1 h before addition of estradiol or insulin increased the pAkt/Akt ratio and FASN expression, and this effect was inhibited by addition of DHA 48 h before rapamycin. Conclusion We conclude that, in MCF-7 cells, DHA inhibits pAKT signaling and thus expression of p-SREBP-1, m-SREBP-1, and FASN and cell proliferation.
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Affiliation(s)
- Li-Hsuan Huang
- Institute of Physiology, College of Medicine, National Taiwan University, 1 Sec 1 Jai-Ai Rd, Taipei, 100, Taiwan
| | - Hsin-Yun Chung
- Institute of Physiology, College of Medicine, National Taiwan University, 1 Sec 1 Jai-Ai Rd, Taipei, 100, Taiwan
| | - Hui-Min Su
- Institute of Physiology, College of Medicine, National Taiwan University, 1 Sec 1 Jai-Ai Rd, Taipei, 100, Taiwan.
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38
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Berkson BM, Calvo Riera F. The Long-Term Survival of a Patient With Stage IV Renal Cell Carcinoma Following an Integrative Treatment Approach Including the Intravenous α-Lipoic Acid/Low-Dose Naltrexone Protocol. Integr Cancer Ther 2017; 17:986-993. [PMID: 29258346 PMCID: PMC6142095 DOI: 10.1177/1534735417747984] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
In this case report, we describe the treatment of a 64-year-old male patient
diagnosed with metastatic renal cell carcinoma (RCC) in June of 2008. In spite
of a left nephrectomy and the standard oncological protocols, the patient
developed a solitary left lung metastasis that continued to grow. He was
informed that given his diagnosis and poor response to conventional therapy, any
further treatment would, at best, be palliative. The patient arrived at the
Integrative Medical Center of New Mexico in August of 2010. He was in very poor
health, weak, and cachectic. An integrative program—developed by one of the
authors using intravenous (IV) α-lipoic acid, IV vitamin C, low-dose naltrexone,
and hydroxycitrate, and a healthy life style program—was initiated. From August
2010 to August 2015, the patient’s RCC with left lung metastasis was followed
closely using computed tomography and positron emission tomography/computed
tomography imaging. His most recent positron emission tomography scan
demonstrated no residual increased glucose uptake in his left lung. After only a
few treatments of IV α-lipoic acid and IV vitamin C, his symptoms began to
improve, and the patient regained his baseline weight. His energy and outlook
improved, and he returned to work. The patient had stable disease with
disappearance of the signs and symptoms of stage IV RCC, a full 9 years
following diagnosis, with a gentle integrative program, which is essentially
free of side effects. As of November 2017 the patient feels well and is working
at his full-time job.
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Affiliation(s)
- Burton M Berkson
- 1 Oklahoma State University, Stillwater, OK, USA.,2 The Integrative Medical Center of New Mexico, Las Cruces, NM, USA
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39
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RNF20 Suppresses Tumorigenesis by Inhibiting the SREBP1c-PTTG1 Axis in Kidney Cancer. Mol Cell Biol 2017; 37:MCB.00265-17. [PMID: 28827316 DOI: 10.1128/mcb.00265-17] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 07/29/2017] [Indexed: 12/21/2022] Open
Abstract
Elevated lipid metabolism promotes cancer cell proliferation. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancers, characterized by ectopic lipid accumulation. However, the relationship between aberrant lipid metabolism and tumorigenesis in ccRCC is not thoroughly understood. Here, we demonstrate that ring finger protein 20 (RNF20) acts as a tumor suppressor in ccRCC. RNF20 overexpression repressed lipogenesis and cell proliferation by inhibiting sterol regulatory element-binding protein 1c (SREBP1c), and SREBP1 suppression, either by knockdown or by the pharmacological inhibitor betulin, attenuated proliferation and cell cycle progression in ccRCC cells. Notably, SREBP1c regulates cell cycle progression by inducing the expression of pituitary tumor-transforming gene 1 (PTTG1), a novel target gene of SREBP1c. Furthermore, RNF20 overexpression reduced tumor growth and lipid storage in xenografts. In ccRCC patients, RNF20 downregulation and SREBP1 activation are markers of poor prognosis. Therefore, RNF20 suppresses tumorigenesis in ccRCC by inhibiting the SREBP1c-PTTG1 axis.
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40
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Luengo A, Gui DY, Vander Heiden MG. Targeting Metabolism for Cancer Therapy. Cell Chem Biol 2017; 24:1161-1180. [PMID: 28938091 PMCID: PMC5744685 DOI: 10.1016/j.chembiol.2017.08.028] [Citation(s) in RCA: 657] [Impact Index Per Article: 82.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 08/06/2017] [Accepted: 08/30/2017] [Indexed: 12/11/2022]
Abstract
Metabolic reprogramming contributes to tumor development and introduces metabolic liabilities that can be exploited to treat cancer. Chemotherapies targeting metabolism have been effective cancer treatments for decades, and the success of these therapies demonstrates that a therapeutic window exists to target malignant metabolism. New insights into the differential metabolic dependencies of tumors have provided novel therapeutic strategies to exploit altered metabolism, some of which are being evaluated in preclinical models or clinical trials. Here, we review our current understanding of cancer metabolism and discuss how this might guide treatments targeting the metabolic requirements of tumor cells.
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Affiliation(s)
- Alba Luengo
- The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Dan Y Gui
- The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Matthew G Vander Heiden
- The Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Dana-Farber Cancer Institute, Boston, MA 02115, USA.
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41
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Oleate but not stearate induces the regulatory phenotype of myeloid suppressor cells. Sci Rep 2017; 7:7498. [PMID: 28790345 PMCID: PMC5548895 DOI: 10.1038/s41598-017-07685-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Accepted: 06/29/2017] [Indexed: 12/11/2022] Open
Abstract
Tumor infiltrating myeloid cells play contradictory roles in the tumor development. Dendritic cells and classical activated macrophages support anti-tumor immune activity via antigen presentation and induction of pro-inflammatory immune responses. Myeloid suppressor cells (MSCs), for instance myeloid derived suppressor cells (MDSCs) or tumor associated macrophages play a critical role in tumor growth. Here, treatment with sodium oleate, an unsaturated fatty acid, induced a regulatory phenotype in the myeloid suppressor cell line MSC-2 and resulted in an increased suppression of activated T cells, paralleled by increased intracellular lipid droplets formation. Furthermore, sodium oleate potentiated nitric oxide (NO) production in MSC-2, thereby increasing their suppressive capacity. In primary polarized bone marrow cells, sodium oleate (C18:1) and linoleate (C18:2), but not stearate (C18:0) were identified as potent FFA to induce a regulatory phenotype. This effect was abrogated in MSC-2 as well as primary cells by specific inhibition of droplets formation while the inhibition of de novo FFA synthesis proved ineffective, suggesting a critical role for exogenous FFA in the functional induction of MSCs. Taken together our data introduce a new unsaturated fatty acid-dependent pathway shaping the functional phenotype of MSCs, facilitating the tumor escape from the immune system.
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Zhang C, Liu J, Huang G, Zhao Y, Yue X, Wu H, Li J, Zhu J, Shen Z, Haffty BG, Hu W, Feng Z. Cullin3-KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression. Genes Dev 2017; 30:1956-70. [PMID: 27664236 PMCID: PMC5066239 DOI: 10.1101/gad.283283.116] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Accepted: 08/16/2016] [Indexed: 12/27/2022]
Abstract
ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Zhang et al. show that Cullin3 (CUL3), a core protein of the CUL3–RING ubiquitin ligase complex, interacts with ACLY through its adaptor protein, KLHL25, to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and tumor growth in lung cancer cells. Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3–RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary, our results identify CUL3–KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis and demonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.
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Affiliation(s)
- Cen Zhang
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Juan Liu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Grace Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, New York University, Tuxedo, New Jersey 10987, USA
| | - Yuhan Zhao
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Xuetian Yue
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Hao Wu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Jun Li
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Junlan Zhu
- Nelson Institute of Environmental Medicine, New York University School of Medicine, New York University, Tuxedo, New Jersey 10987, USA
| | - Zhiyuan Shen
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Bruce G Haffty
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers University, The State University of New Jersey, New Brunswick, New Jersey 08903, USA; Department of Pharmacology, Rutgers University, The State University of New Jersey, Piscataway, New Jersey 08854, USA
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Jones JEC, Esler WP, Patel R, Lanba A, Vera NB, Pfefferkorn JA, Vernochet C. Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells. PLoS One 2017; 12:e0169566. [PMID: 28081256 PMCID: PMC5231342 DOI: 10.1371/journal.pone.0169566] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Accepted: 12/19/2016] [Indexed: 11/19/2022] Open
Abstract
Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.
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Affiliation(s)
- Jessica E. C. Jones
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
| | - William P. Esler
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
- * E-mail: (CV); (WPE)
| | - Rushi Patel
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
| | - Adhiraj Lanba
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
| | - Nicholas B. Vera
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
| | - Jeffrey A. Pfefferkorn
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
| | - Cecile Vernochet
- Cardiovascular, Metabolic, and Endocrine Diseases (CVMED) Research Unit, Pfizer Inc, Cambridge, Massachusetts, United States of America
- * E-mail: (CV); (WPE)
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Cha JY, Lee HJ. Targeting Lipid Metabolic Reprogramming as Anticancer Therapeutics. J Cancer Prev 2016; 21:209-215. [PMID: 28053954 PMCID: PMC5207604 DOI: 10.15430/jcp.2016.21.4.209] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Revised: 11/25/2016] [Accepted: 11/26/2016] [Indexed: 01/08/2023] Open
Abstract
Cancer cells rewire their metabolism to satisfy the demands of growth and survival, and this metabolic reprogramming has been recognized as an emerging hallmark of cancer. Lipid metabolism is pivotal in cellular process that converts nutrients into energy, building blocks for membrane biogenesis and the generation of signaling molecules. Accumulating evidence suggests that cancer cells show alterations in different aspects of lipid metabolism. The changes in lipid metabolism of cancer cells can affect numerous cellular processes, including cell growth, proliferation, differentiation, and survival. The potential dependence of cancer cells on the deregulated lipid metabolism suggests that enzymes and regulating factors involved in this process are promising targets for cancer treatment. In this review, we focus on the features associated with the lipid metabolic pathways in cancer, and highlight recent advances on the therapeutic targets of specific lipid metabolic enzymes or regulating factors and target-directed small molecules that can be potentially used as anticancer drugs.
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Affiliation(s)
- Ji-Young Cha
- Department of Biochemistry, Gachon University College of Medicine, Incheon, Korea
| | - Ho-Jae Lee
- Department of Biochemistry, Gachon University College of Medicine, Incheon, Korea
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Wilmanski T, Buhman K, Donkin SS, Burgess JR, Teegarden D. 1α,25-dihydroxyvitamin D inhibits de novo fatty acid synthesis and lipid accumulation in metastatic breast cancer cells through down-regulation of pyruvate carboxylase. J Nutr Biochem 2016; 40:194-200. [PMID: 27936456 DOI: 10.1016/j.jnutbio.2016.11.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 10/18/2016] [Accepted: 11/14/2016] [Indexed: 02/01/2023]
Abstract
Both increased de novo fatty acid synthesis and higher neutral lipid accumulation are a common phenotype observed in aggressive breast cancer cells, making lipid metabolism a promising target for breast cancer prevention. In the present studies, we demonstrate a novel effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D (1,25(OH)₂D) on lipid metabolism in malignant breast epithelial cells. Treatment of MCF10CA1a breast epithelial cells with 1,25(OH)₂D (10 nM) for 5 and 7 days decreased the level of triacylglycerol, the most abundant form of neutral lipids, by 20%(±3.9) and 50%(±5.9), respectively. In addition, 1,25(OH)₂D treatment for 5 days decreased palmitate synthesis from glucose, the major fatty acid synthesized de novo (48%±5.5 relative to vehicle). We have further identified the anaplerotic enzyme pyruvate carboxylase (PC) as a target of 1,25(OH)₂D-mediated regulation and hypothesized that 1,25(OH)₂D regulates breast cancer cell lipid metabolism through inhibition of PC. PC mRNA expression was down-regulated with 1,25(OH)₂D treatment at 2 (73%±6 relative to vehicle) and 5 (56%±8 relative to vehicle) days. Decrease in mRNA abundance corresponded with a decrease in PC protein expression at 5 days of treatment (54%±12 relative to vehicle). Constitutive overexpression of PC in MCF10CA1a cells using a pCMV6-PC plasmid inhibited the effect of 1,25(OH)₂D on both TAG accumulation and de novo palmitate synthesis from glucose. Together, these studies demonstrate a novel mechanism through which 1,25(OH)₂D regulates lipid metabolism in malignant breast epithelial cells.
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Affiliation(s)
- Tomasz Wilmanski
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN
| | - Kimberly Buhman
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN
| | - Shawn S Donkin
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN
| | - John R Burgess
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN
| | - Dorothy Teegarden
- Department of Nutrition Science, Interdepartmental Nutrition Program, Purdue University, West Lafayette, IN.
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Abstract
Lipid metabolism, in particular the synthesis of fatty acids (FAs), is an essential cellular process that converts nutrients into metabolic intermediates for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression. FA synthesis has received substantial attention as a potential target for cancer therapy, but strategies to target this process have not yet translated into clinical practice. Furthermore, efforts to target this pathway must consider the influence of the tumour microenvironment.
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Affiliation(s)
- Florian Röhrig
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, Josef-Schneider-Strasse 6, 97080 Würzburg, Germany
| | - Almut Schulze
- Department of Biochemistry and Molecular Biology, Theodor Boveri Institute, Biocenter, Am Hubland, 97074 Würzburg, Germany
- Comprehensive Cancer Center Mainfranken, Josef-Schneider-Strasse 6, 97080 Würzburg, Germany
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47
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Li G, Li M, Hu J, Lei R, Xiong H, Ji H, Yin H, Wei Q, Hu G. The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis. Oncogene 2016; 36:989-998. [PMID: 27641336 DOI: 10.1038/onc.2016.265] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Revised: 05/17/2016] [Accepted: 06/17/2016] [Indexed: 02/08/2023]
Abstract
Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells. Suppression of lipogenesis by silencing ATP citrate lyase (ACLY) and fatty acid synthase (FASN) or by chemical inhibitors diminishes the effects of miR-182-PDK4 in tumor growth. Alteration of de novo lipogenesis also affects reactive oxygen species (ROS) production and the downstream JNK signaling pathway. Hence, our work suggests that the miR-182-PDK4 axis is a crucial regulator of cancer cell metabolism and a potential target for antitumor therapy.
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Affiliation(s)
- G Li
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China
| | - M Li
- The Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - J Hu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China
| | - R Lei
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China
| | - H Xiong
- Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - H Ji
- The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - H Yin
- The Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Q Wei
- Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - G Hu
- The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China
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48
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Yao CH, Fowle-Grider R, Mahieu NG, Liu GY, Chen YJ, Wang R, Singh M, Potter GS, Gross RW, Schaefer J, Johnson SL, Patti GJ. Exogenous Fatty Acids Are the Preferred Source of Membrane Lipids in Proliferating Fibroblasts. Cell Chem Biol 2016; 23:483-93. [PMID: 27049668 PMCID: PMC5510604 DOI: 10.1016/j.chembiol.2016.03.007] [Citation(s) in RCA: 104] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Revised: 02/11/2016] [Accepted: 03/11/2016] [Indexed: 12/11/2022]
Abstract
Cellular proliferation requires the formation of new membranes. It is often assumed that the lipids needed for these membranes are synthesized mostly de novo. Here, we show that proliferating fibroblasts prefer to take up palmitate from the extracellular environment over synthesizing it de novo. Relative to quiescent fibroblasts, proliferating fibroblasts increase their uptake of palmitate, decrease fatty acid degradation, and instead direct more palmitate to membrane lipids. When exogenous palmitate is provided in the culture media at physiological concentrations, de novo synthesis accounts for only a minor fraction of intracellular palmitate in proliferating fibroblasts as well as proliferating HeLa and H460 cells. Blocking fatty acid uptake decreased the proliferation rate of fibroblasts, HeLa, and H460 cells, while supplementing media with exogenous palmitate resulted in decreased glucose uptake and rendered cells less sensitive to glycolytic inhibition. Our results suggest that cells scavenging exogenous lipids may be less susceptible to drugs targeting glycolysis and de novo lipid synthesis.
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Affiliation(s)
- Cong-Hui Yao
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Ronald Fowle-Grider
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Nathanial G Mahieu
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Gao-Yuan Liu
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Division of Bioorganic and Molecular Pharmacology, Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA
| | - Ying-Jr Chen
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Rencheng Wang
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA; Department of Genetics, Washington University, St. Louis, MO 63110, USA
| | - Manmilan Singh
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Gregory S Potter
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Richard W Gross
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Division of Bioorganic and Molecular Pharmacology, Department of Internal Medicine, Washington University, St. Louis, MO 63110, USA
| | - Jacob Schaefer
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA
| | - Stephen L Johnson
- Department of Genetics, Washington University, St. Louis, MO 63110, USA
| | - Gary J Patti
- Department of Chemistry, Washington University, St. Louis, MO 63130, USA; Department of Medicine, Washington University, St. Louis, MO 63110, USA.
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49
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Potze L, Di Franco S, Grandela C, Pras-Raves ML, Picavet DI, van Veen HA, van Lenthe H, Mullauer FB, van der Wel NN, Luyf A, van Kampen AHC, Kemp S, Everts V, Kessler JH, Vaz FM, Medema JP. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene 2015; 35:427-37. [PMID: 25893306 DOI: 10.1038/onc.2015.102] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 01/02/2015] [Accepted: 01/21/2015] [Indexed: 12/23/2022]
Abstract
Cancer is associated with strong changes in lipid metabolism. For instance, normal cells take up fatty acids (FAs) from the circulation, while tumour cells generate their own and become dependent on de novo FA synthesis, which could provide a vulnerability to target tumour cells. Betulinic acid (BetA) is a natural compound that selectively kills tumour cells through an ill-defined mechanism that is independent of BAX and BAK, but depends on mitochondrial permeability transition-pore opening. Here we unravel this pathway and show that BetA inhibits the activity of steroyl-CoA-desaturase (SCD-1). This enzyme is overexpressed in tumour cells and critically important for cells that utilize de novo FA synthesis as it converts newly synthesized saturated FAs to unsaturated FAs. Intriguingly, we find that inhibition of SCD-1 by BetA or, alternatively, with a specific SCD-1 inhibitor directly and rapidly impacts on the saturation level of cardiolipin (CL), a mitochondrial lipid that has important structural and metabolic functions and at the same time regulates mitochondria-dependent cell death. As a result of the enhanced CL saturation mitochondria of cancer cells, but not normal cells that do not depend on de novo FA synthesis, undergo ultrastructural changes, release cytochrome c and quickly induce cell death. Importantly, addition of unsaturated FAs circumvented the need for SCD-1 activity and thereby prevented BetA-induced CL saturation and subsequent cytotoxicity, supporting the importance of this novel pathway in the cytotoxicity induced by BetA.
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Affiliation(s)
- L Potze
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - S Di Franco
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands.,Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Palermo, Italy
| | - C Grandela
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - M L Pras-Raves
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - D I Picavet
- Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - H A van Veen
- Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - H van Lenthe
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - F B Mullauer
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - N N van der Wel
- Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - A Luyf
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - A H C van Kampen
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Bioinformatics Laboratory, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - S Kemp
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - V Everts
- Department of Cell Biology and Histology, Core facility Cellular Imaging University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - J H Kessler
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - F M Vaz
- Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
| | - J P Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental and Molecular Medicine, University of Amsterdam, Academic Medical Center (AMC), Amsterdam, The Netherlands
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50
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Sborov DW, Haverkos BM, Harris PJ. Investigational cancer drugs targeting cell metabolism in clinical development. Expert Opin Investig Drugs 2015; 24:79-94. [PMID: 25224845 PMCID: PMC4434605 DOI: 10.1517/13543784.2015.960077] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Introduction: Malignant cell transformation and tumor progression are associated with alterations in glycolysis, fatty acid synthesis, amino acid delivery and production of reactive oxygen species. With increased understanding of the role of metabolism in tumors, there has been interest in developing agents that target tumor specific metabolic pathways. Numerous promising agents targeting altered metabolic pathways are currently in Phase I - III clinical trials. Areas covered: This paper reviews the early phase clinical trial development of these agents and provides perspective on the future direction of this emerging field. Specifically, the authors describe novel and repurposed therapies, focusing on the effects of each agent on tumor metabolism and results from relevant Phase I and II clinical trials. Expert opinion: Metabolism modulating agents, alone and in combinations with other classes of agents, have shown efficacy in the treatment of neoplasm, which, the authors believe, will bear positive results in future studies. Because of the significant crosstalk between metabolic pathways and oncogenic signaling pathways, the authors also believe that combining metabolic modifiers with targeted agents will be an important strategy. An increased understanding of cancer metabolism, in addition to the continued study of metabolic modulators, should lead to further advances in this nascent therapeutic field in the future.
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Affiliation(s)
- Douglas W Sborov
- Ohio State University, Department of Internal Medicine, Columbus, OH, USA
| | - Bradley M Haverkos
- Ohio State University, Department of Internal Medicine, Columbus, OH, USA
| | - Pamela J Harris
- National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr, Rockville, MD 20850-9739, USA Tel: +1 240 276 6565; Fax: +1 240 276 7894;
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