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Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: molecular basis and pathophysiological consequences

Oncogene volume 36, pages 6030–6040 (2017)Cite this article

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Abstract

Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer.

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References

  1. Dang CV, Semenza GL . Oncogenic alterations of metabolism. Trends Biochem Sci 1999; 24: 68–72.

    Article  CAS  PubMed  Google Scholar 

  2. Dang CV . Links between metabolism and cancer. Genes Dev 2012; 26: 877–890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Modica-Napolitano JS, Singh KK . Mitochondrial dysfunction in cancer. Mitochondrion 2004; 4: 755–762.

    Article  CAS  PubMed  Google Scholar 

  4. DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S et al. Beyond aerobic glycolysis: Transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci 2007; 104: 19345–19350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Semenza GL . HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev 2010; 20: 51–56.

    Article  CAS  PubMed  Google Scholar 

  6. Shanware NP, Mullen AR, DeBerardinis RJ, Abraham RT . Glutamine: pleiotropic roles in tumor growth and stress resistance. J Mol Med (Berl) 2011; 89: 229–236.

    Article  CAS  Google Scholar 

  7. DeBerardinis RJ . Is cancer a disease of abnormal cellular metabolism? New angles on an old idea. Genet Med 2008; 10: 767–777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. McDunn JE, Li Z, Adam KP, Neri BP, Wolfert RL, Milburn MV et al. Metabolomic signatures of aggressive prostate cancer. Prostate 2013; 73: 1547–1560.

    Article  CAS  PubMed  Google Scholar 

  9. Sreekumar A, Poisson LM, Rajendiran TM, Khan AP, Cao Q, Yu J et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 2009; 457: 910–914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Teahan O, Bevan CL, Waxman J, Keun HC . Metabolic signatures of malignant progression in prostate epithelial cells. Int J Biochem Cell Biol 2011; 43: 1002–1009.

    Article  CAS  PubMed  Google Scholar 

  11. Costello LC, Franklin RB . The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology 2000; 59: 269–282.

    Article  CAS  PubMed  Google Scholar 

  12. Costello LC, Franklin RB . 'Why do tumour cells glycolyse?': from glycolysis through citrate to lipogenesis. Mol Cell Biochem 2005; 280: 1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu Y . Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis 2006; 9: 230–234.

    Article  CAS  PubMed  Google Scholar 

  14. Liu Y, Zuckier LS, Ghesani NV . Dominant uptake of fatty acid over glucose by prostate cells: a potential new diagnostic and therapeutic approach. Anticancer Res 2010; 30: 369–374.

    PubMed  Google Scholar 

  15. Schlaepfer IR, Glode LM, Hitz CA, Pac CT, Boyle KE, Maroni P et al. Inhibition of lipid oxidation increases glucose metabolism and enhances 2-Deoxy-2-[(18)F]Fluoro-D-glucose uptake in prostate cancer mouse xenografts. Mol Imaging Biol 2015; 17: 529–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wu X, Daniels G, Lee P, Monaco ME . Lipid metabolism in prostate cancer. Am J Clin Exp Urol 2014; 2: 111–120.

    PubMed  PubMed Central  Google Scholar 

  17. Bastin J . Regulation of mitochondrial fatty acid beta-oxidation in human: what can we learn from inborn fatty acid beta-oxidation deficiencies? Biochimie 2014; 96: 113–120.

    Article  CAS  PubMed  Google Scholar 

  18. Foster DW . The role of the carnitine system in human metabolism. Ann N Y Acad Sci 2004; 1033: 1–16.

    Article  CAS  PubMed  Google Scholar 

  19. Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J . Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol Aspects Med 2004; 25: 495–520.

    Article  CAS  PubMed  Google Scholar 

  20. Ramsay RR, Gandour RD, van der Leij FR . Molecular enzymology of carnitine transfer and transport. Biochim Biophys Acta 2001; 1546: 21–43.

    Article  CAS  PubMed  Google Scholar 

  21. Jogl G, Hsiao YS, Tong L . Structure and function of carnitine acyltransferases. Ann N Y Acad Sci 2004; 1033: 17–29.

    Article  CAS  PubMed  Google Scholar 

  22. Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.

    Article  CAS  PubMed  Google Scholar 

  23. Khanmi K, Ignacimuthu S, Paulraj MG . MicroRNA in prostate cancer. Clin Chim Acta 2015; 451: 154–160.

    Article  CAS  PubMed  Google Scholar 

  24. Kurisetty VV, Lakshmanaswamy R, Damodaran C . Pathogenic and therapeutic role of miRNAs in breast cancer. Front Biosci (Landmark Ed) 2014; 19: 1–11.

    Article  CAS  Google Scholar 

  25. Liu X, Chen X, Yu X, Tao Y, Bode AM, Dong Z et al. Regulation of microRNAs by epigenetics and their interplay involved in cancer. J Exp Clin Cancer Res 2013; 32: 96.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR . Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol 2002; 168: 273–280.

    Article  PubMed  Google Scholar 

  27. Arora A, Singh S, Bhatt AN, Pandey S, Sandhir R, Dwarakanath BS . Interplay Between Metabolism and Oncogenic Process: Role of microRNAs. Transl Oncogenomics 2015; 7: 11–27.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pinweha P, Rattanapornsompong K, Charoensawan V, Jitrapakdee S . MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers. Comput Struct Biotechnol J 2016; 14: 223–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Love MI, Huber W, Anders S . Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 2014; 15: 550.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cardenas-Navia LI, Mace D, Richardson RA, Wilson DF, Shan S, Dewhirst MW . The pervasive presence of fluctuating oxygenation in tumors. Cancer Res 2008; 68: 5812–5819.

    Article  CAS  PubMed  Google Scholar 

  31. Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F et al. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res 2008; 68: 6162–6170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T . MicroRNA expression profiling in prostate cancer. Cancer Res 2007; 67: 6130–6135.

    Article  CAS  PubMed  Google Scholar 

  33. Song C, Chen H, Wang T, Zhang W, Ru G, Lang J . Expression profile analysis of microRNAs in prostate cancer by next-generation sequencing. Prostate 2015; 75: 500–516.

    Article  CAS  PubMed  Google Scholar 

  34. Schaefer A, Jung M, Kristiansen G, Lein M, Schrader M, Miller K et al. MicroRNAs and cancer: current state and future perspectives in urologic oncology. Urol Oncol 2010; 28: 4–13.

    Article  CAS  PubMed  Google Scholar 

  35. Gill BS, Alex JM, Navgeet, Kumar S . Missing link between microRNA and prostate cancer. Tumour Biol 2016; 37: 5683–5704.

    Article  CAS  PubMed  Google Scholar 

  36. Li X, Chen YT, Josson S, Mukhopadhyay NK, Kim J, Freeman MR et al. MicroRNA-185 and 342 inhibit tumorigenicity and induce apoptosis through blockade of the SREBP metabolic pathway in prostate cancer cells. PLoS One 2013; 8: e70987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dong P, Ihira K, Xiong Y, Watari H, Hanley SJ, Yamada T et al. Reactivation of epigenetically silenced miR-124 reverses the epithelial-to-mesenchymal transition and inhibits invasion in endometrial cancer cells via the direct repression of IQGAP1 expression. Oncotarget 2016; 7: 20260–20270.

    PubMed  PubMed Central  Google Scholar 

  38. Wang X, Liu Y, Liu X, Yang J, Teng G, Zhang L et al. MiR-124 inhibits cell proliferation, migration and invasion by directly targeting SOX9 in lung adenocarcinoma. Oncol Rep 2016; 35: 3115–3121.

    Article  CAS  PubMed  Google Scholar 

  39. Shi XB, Ma AH, Xue L, Li M, Nguyen HG, Yang JC et al. miR-124 and Androgen Receptor Signaling Inhibitors Repress Prostate Cancer Growth by Downregulating Androgen Receptor Splice Variants, EZH2, and Src. Cancer Res 2015; 75: 5309–5317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Eaton S . Control of mitochondrial beta-oxidation flux. Prog Lipid Res 2002; 41: 197–239.

    Article  CAS  PubMed  Google Scholar 

  41. Shen N, Huang X, Li J . Upregulation of miR-129-5p affects laryngeal cancer cell proliferation, invasiveness, and migration by affecting STAT3 expression. Tumour Biol 2016; 37: 1789–1796.

    Article  CAS  PubMed  Google Scholar 

  42. Dossing KB, Binderup T, Kaczkowski B, Jacobsen A, Rossing M, Winther O et al. Down-Regulation of miR-129-5p and the let-7 Family in Neuroendocrine Tumors and Metastases Leads to Up-Regulation of Their Targets Egr1, G3bp1, Hmga2 and Bach1. Genes (Basel) 2015; 6: 1–21.

    Article  Google Scholar 

  43. Shen R, Pan S, Qi S, Lin X, Cheng S . Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 in gastric cancer. Biochem Biophys Res Commun 2010; 394: 1047–1052.

    Article  CAS  PubMed  Google Scholar 

  44. Duan L, Hao X, Liu Z, Zhang Y, Zhang G . MiR-129-5p is down-regulated and involved in the growth, apoptosis and migration of medullary thyroid carcinoma cells through targeting RET. FEBS Lett 2014; 588: 1644–1651.

    Article  CAS  PubMed  Google Scholar 

  45. Ma N, Chen F, Shen SL, Chen W, Chen LZ, Su Q et al. MicroRNA-129-5p inhibits hepatocellular carcinoma cell metastasis and invasion via targeting ETS1. Biochem Biophys Res Commun 2015; 461: 618–623.

    Article  CAS  PubMed  Google Scholar 

  46. Palmieri F, Pierri CL . Mitochondrial metabolite transport. Essays Biochem 2010; 47: 37–52.

    Article  CAS  PubMed  Google Scholar 

  47. Eichner LJ, Perry MC, Dufour CR, Bertos N, Park M, St-Pierre J et al. miR-378(*) mediates metabolic shift in breast cancer cells via the PGC-1beta/ERRgamma transcriptional pathway. Cell Metab 2010; 12: 352–361.

    Article  CAS  PubMed  Google Scholar 

  48. Riehle C, Abel ED . PGC-1 proteins and heart failure. Trends Cardiovasc Med 2012; 22: 98–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Carrer M, Liu N, Grueter CE, Williams AH, Frisard MI, Hulver MW et al. Control of mitochondrial metabolism and systemic energy homeostasis by microRNAs 378 and 378*. Proc Natl Acad Sci USA 2012; 109: 15330–15335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lu J, Tan M, Cai Q . The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism. Cancer Lett 2015; 356: 156–164.

    Article  CAS  PubMed  Google Scholar 

  51. Schlaepfer IR, Rider L, Rodrigues LU, Gijon MA, Pac CT, Romero L et al. Lipid catabolism via CPT1 as a therapeutic target for prostate cancer. Mol Cancer Ther 2014; 13: 2361–2371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Johnson IR, Parkinson-Lawrence EJ, Butler LM, Brooks DA . Prostate cell lines as models for biomarker discovery: performance of current markers and the search for new biomarkers. Prostate 2014; 74: 547–560.

    Article  CAS  PubMed  Google Scholar 

  53. Berthon P, Cussenot O, Hopwood L, Leduc A, Maitland N . Functional expression of sv40 in normal human prostatic epithelial and fibroblastic cells - differentiation pattern of nontumorigenic cell-lines. Int J Oncol 1995; 6: 333–343.

    CAS  PubMed  Google Scholar 

  54. Fritz V, Benfodda Z, Henriquet C, Hure S, Cristol JP, Michel F et al. Metabolic intervention on lipid synthesis converging pathways abrogates prostate cancer growth. Oncogene 2013; 32: 5101–5110.

    Article  CAS  PubMed  Google Scholar 

  55. Giordano A, Calvani M, Petillo O, Grippo P, Tuccillo F, Melone MA et al. tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1. Cell Death Differ 2005; 12: 603–613.

    Article  CAS  PubMed  Google Scholar 

  56. Priore P, Giudetti AM, Natali F, Gnoni GV, Geelen MJ . Metabolism and short-term metabolic effects of conjugated linoleic acids in rat hepatocytes. Biochim Biophys Acta 2007; 1771: 1299–1307.

    Article  CAS  PubMed  Google Scholar 

  57. Peluso G, Petillo O, Margarucci S, Mingrone G, Greco AV, Indiveri C et al. Decreased mitochondrial carnitine translocase in skeletal muscles impairs utilization of fatty acids in insulin-resistant patients. Front Biosci 2002; 7: a109–a116.

    Article  CAS  PubMed  Google Scholar 

  58. IJlst L, van Roermund CW, Iacobazzi V, Oostheim W, Ruiter JP, Williams JC et al. Functional analysis of mutant human carnitine acylcarnitine translocases in yeast. Biochem Biophys Res Commun 2001; 280: 700–706.

    Article  CAS  PubMed  Google Scholar 

  59. Muoio DM, Noland RC, Kovalik JP, Seiler SE, Davies MN, DeBalsi KL et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 2012; 15: 764–777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Brass EP, Hoppel CL . Relationship between acid-soluble carnitine and coenzyme A pools in vivo. Biochem J 1980; 190: 495–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kim JY, Hickner RC, Cortright RL, Dohm GL, Houmard JA . Lipid oxidation is reduced in obese human skeletal muscle. Am J Physiol Endocrinol Metab 2000; 279: E1039–E1044.

    Article  CAS  PubMed  Google Scholar 

  62. Shahabi A, Lewinger JP, Ren J, April C, Sherrod AE, Hacia JG et al. Novel gene expression signature predictive of clinical recurrence after radical prostatectomy in early stage prostate cancer patients. Prostate 2016; 76: 1239–1256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported from Ministero dell’Istruzione, dell’Università e della Ricerca of Italy, Progetto PON – ‘Ricerca e Competitività 2007–2013’—PON01_01802: ‘Sviluppo di molecole capaci di modulare vie metaboliche intracellulari redox-sensibili per la prevenzione e la cura di patologie infettive, tumorali, neurodegenerative e loro delivery mediante piattaforme nano tecnologiche’, and PON01_02512: ‘Ricerca e sviluppo di bioregolatori attivi sui meccanismi epigenetici dei processi infiammatori nelle malattie croniche e degenerative’. Precis: this study reports the critical role of specific miRNAs (hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378) to sustain prostate cancer metabolic flexibility via modulation of CPT1A, CACT and CrAT expression.

Author contributions

Conception and design: G Peluso, A Valentino, A Calarco, A Di Salle. Development of methodology: A Valentino, M Finicelli, S Margarucci, A Calarco, A Di Salle, RA Calogero. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A Sciarra, A Gentilucci. Analysis and interpretation of data (for example, statistical analysis, biostatistics, computational analysis): S Crispi, RA Calogero, A Valentino. Writing, review and/or revision of the manuscript: A Valentino, A Calarco, A Di Salle, U Galderisi, G Peluso. Study supervision: U Galderisi, G Peluso.

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Authors and Affiliations

  1. Institute of Agro-environmental and Forest Biology, National Research Council, IBAF – CNR, Naples, Italy

    A Valentino, A Calarco, A Di Salle & G Peluso

  2. Institute of Bioscience and BioResources – CNR, Naples, Italy

    M Finicelli, S Crispi & S Margarucci

  3. Department of Molecular Biotechnology and Health Sciences, Laboratory of Immunology, University of Turin, Turin, Italy

    R A Calogero & F Riccardo

  4. Department Urology, Prostate Cancer Unit, University ‘Sapienza’, Policlinico Umberto I, Rome, Italy

    A Sciarra & A Gentilucci

  5. Department of Experimental Medicine, Biotechnology and Molecular Biology Section, University of Campania ‘Luigi Vanvitelli’, Naples, Italy

    U Galderisi

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Valentino, A., Calarco, A., Di Salle, A. et al. Deregulation of MicroRNAs mediated control of carnitine cycle in prostate cancer: molecular basis and pathophysiological consequences. Oncogene 36, 6030–6040 (2017). https://doi.org/10.1038/onc.2017.216

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