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Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death

Oncogene volume 34, pages 3264–3272 (2015)Cite this article

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Abstract

Blockade of fatty acid synthase (FASN), a key enzyme involved in de novo lipogenesis, results in robust death of ovarian cancer cells. However, known FASN inhibitors have proven to be poor therapeutic agents due to their ability to induce cachexia. Therefore, we sought to identify additional targets in the pathway linking FASN inhibition and cell death whose modulation might kill ovarian cancer cells without the attendant side effects. Here, we show that the initiator caspase-2 is required for robust death of ovarian cancer cells induced by FASN inhibitors. REDD1 (also known as Rtp801 or DDIT4), a known mTOR inhibitor previously implicated in the response to FASN inhibition, is a novel caspase-2 regulator in this pathway. REDD1 induction is compromised in ovarian cancer cells that do not respond to FASN inhibition. Inhibition of FASN induced an ATF4-dependent transcriptional induction of REDD1; downregulation of REDD1 prevented orlistat-induced activation of caspase-2, as monitored by its cleavage, proteolytic activity and dimerization. Abrogation of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian cancer cells (OVCA420 cells) from orlistat-induced death. Conversely, suppression of mTOR with the chemical inhibitors PP242 or rapamycin-sensitized DOV13, an ovarian cancer cell line incapable of inducing REDD1, to orlistat-induced cell death through caspase-2. These findings indicate that REDD1 positively controls caspase-2-dependent cell death of ovarian cancer cells by inhibiting mTOR, placing mTOR as a novel upstream regulator of caspase-2 and supporting the possibility of manipulating mTOR to enhance caspase-2 activation in ovarian cancer.

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References

  1. Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.

    Article  CAS  Google Scholar 

  2. Schulze A, Harris AL . How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature 2012; 491: 364–373.

    Article  CAS  Google Scholar 

  3. Hsu PP, Sabatini DM . Cancer cell metabolism: Warburg and beyond. Cell 2008; 134: 703–707.

    Article  CAS  Google Scholar 

  4. Santos CR, Schulze A . Lipid metabolism in cancer. FEBS J 2012; 279: 2610–2623.

    Article  CAS  Google Scholar 

  5. Menendez JA, Lupu R . Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007; 7: 763–777.

    Article  CAS  Google Scholar 

  6. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr . Cellular fatty acid metabolism and cancer. Cell Metab 2013; 18: 153–161.

    Article  CAS  Google Scholar 

  7. Little JL, Wheeler FB, Fels DR, Koumenis C, Kridel SJ . Inhibition of fatty acid synthase induces endoplasmic reticulum stress in tumor cells. Cancer Res 2007; 67: 1262–1269.

    Article  CAS  Google Scholar 

  8. Alo PL, Visca P, Framarino ML, Botti C, Monaco S, Sebastiani V et al. Immunohistochemical study of fatty acid synthase in ovarian neoplasms. Oncol Rep 2000; 7: 1383–1388.

    CAS  PubMed  Google Scholar 

  9. Gansler TS, Hardman W 3rd, Hunt DA, Schaffel S, Hennigar RA . Increased expression of fatty acid synthase (OA-519) in ovarian neoplasms predicts shorter survival. Hum Pathol 1997; 28: 686–692.

    Article  CAS  Google Scholar 

  10. Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011; 17: 1498–1503.

    Article  CAS  Google Scholar 

  11. Zhou W, Han WF, Landree LE, Thupari JN, Pinn ML, Bililign T et al. Fatty acid synthase inhibition activates AMP-activated protein kinase in SKOV3 human ovarian cancer cells. Cancer Res 2007; 67: 2964–2971.

    Article  CAS  Google Scholar 

  12. Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T et al. Fatty acid synthase expression associated with NAC1 is a potential therapeutic target in ovarian clear cell carcinomas. Br J Cancer 2012; 107: 300–307.

    Article  CAS  Google Scholar 

  13. Tomek K, Wagner R, Varga F, Singer CF, Karlic H, Grunt TW . Blockade of fatty acid synthase induces ubiquitination and degradation of phosphoinositide-3-kinase signaling proteins in ovarian cancer. Mol Cancer Res 2011; 9: 1767–1779.

    Article  CAS  Google Scholar 

  14. Bergeron L, Perez GI, Macdonald G, Shi L, Sun Y, Jurisicova A et al. Defects in regulation of apoptosis in caspase-2-deficient mice. Genes Dev 1998; 12: 1304–1314.

    Article  CAS  Google Scholar 

  15. Zhang Y, Padalecki SS, Chaudhuri AR, De Waal E, Goins BA, Grubbs B et al. Caspase-2 deficiency enhances aging-related traits in mice. Mech Ageing Dev 2007; 128: 213–221.

    Article  CAS  Google Scholar 

  16. Puccini J, Shalini S, Voss AK, Gatei M, Wilson CH, Hiwase DK et al. Loss of caspase-2 augments lymphomagenesis and enhances genomic instability in Atm-deficient mice. Proc Natl Acad Sci USA 2013; 110: 19920–19925.

    Article  CAS  Google Scholar 

  17. Ho LH, Taylor R, Dorstyn L, Cakouros D, Bouillet P, Kumar S . A tumor suppressor function for caspase-2. Proc Natl Acad Sci USA 2009; 106: 5336–5341.

    Article  CAS  Google Scholar 

  18. Parsons MJ, McCormick L, Janke L, Howard A, Bouchier-Hayes L, Green DR . Genetic deletion of caspase-2 accelerates MMTV/c-neu-driven mammary carcinogenesis in mice. Cell Death Differ 2013; 20: 1174–1182.

    Article  CAS  Google Scholar 

  19. Andersen JL, Thompson JW, Lindblom KR, Johnson ES, Yang CS, Lilley LR et al. A biotin switch-based proteomics approach identifies 14-3-3zeta as a target of Sirt1 in the metabolic regulation of caspase-2. Mol Cell 2011; 43: 834–842.

    Article  CAS  Google Scholar 

  20. Nutt LK, Margolis SS, Jensen M, Herman CE, Dunphy WG, Rathmell JC et al. Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2. Cell 2005; 123: 89–103.

    Article  CAS  Google Scholar 

  21. Bouchier-Hayes L . The role of caspase-2 in stress-induced apoptosis. J Cell Mol Med 2010; 14: 1212–1224.

    Article  CAS  Google Scholar 

  22. Ho LH, Read SH, Dorstyn L, Lambrusco L, Kumar S . Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 2008; 27: 3393–3404.

    Article  CAS  Google Scholar 

  23. Vakifahmetoglu H, Olsson M, Tamm C, Heidari N, Orrenius S, Zhivotovsky B . DNA damage induces two distinct modes of cell death in ovarian carcinomas. Cell Death Differ 2008; 15: 555–566.

    Article  CAS  Google Scholar 

  24. Bonzon C, Bouchier-Hayes L, Pagliari LJ, Green DR, Newmeyer DD . Caspase-2-induced apoptosis requires bid cleavage: a physiological role for bid in heat shock-induced death. Mol Biol Cell 2006; 17: 2150–2157.

    Article  CAS  Google Scholar 

  25. Guo Y, Srinivasula SM, Druilhe A, Fernandes-Alnemri T, Alnemri ES . Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. J Biol Chem 2002; 277: 13430–13437.

    Article  CAS  Google Scholar 

  26. Lin CF, Chen CL, Chang WT, Jan MS, Hsu LJ, Wu RH et al. Sequential caspase-2 and caspase-8 activation upstream of mitochondria during ceramide and etoposide-induced apoptosis. J Biol Chem 2004; 279: 40755–40761.

    Article  CAS  Google Scholar 

  27. Shin S, Lee Y, Kim W, Ko H, Choi H, Kim K . Caspase-2 primes cancer cells for TRAIL-mediated apoptosis by processing procaspase-8. EMBO J 2005; 24: 3532–3542.

    Article  CAS  Google Scholar 

  28. Baliga BC, Read SH, Kumar S . The biochemical mechanism of caspase-2 activation. Cell Death Differ 2004; 11: 1234–1241.

    Article  CAS  Google Scholar 

  29. Tinel A, Tschopp J . The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 2004; 304: 843–846.

    Article  CAS  Google Scholar 

  30. Ribe EM, Jean YY, Goldstein RL, Manzl C, Stefanis L, Villunger A et al. Neuronal caspase 2 activity and function requires RAIDD, but not PIDD. Biochem J 2012; 444: 591–599.

    Article  CAS  Google Scholar 

  31. Manzl C, Krumschnabel G, Bock F, Sohm B, Labi V, Baumgartner F et al. Caspase-2 activation in the absence of PIDDosome formation. J Cell Biol 2009; 185: 291–303.

    Article  CAS  Google Scholar 

  32. Bouchier-Hayes L, Oberst A, McStay GP, Connell S, Tait SW, Dillon CP et al. Characterization of cytoplasmic caspase-2 activation by induced proximity. Mol Cell 2009; 35: 830–840.

    Article  CAS  Google Scholar 

  33. Nutt LK, Buchakjian MR, Gan E, Darbandi R, Yoon SY, Wu JQ et al. Metabolic control of oocyte apoptosis mediated by 14-3-3zeta-regulated dephosphorylation of caspase-2. Dev Cell 2009; 16: 856–866.

    Article  CAS  Google Scholar 

  34. Knowles LM, Yang C, Osterman A, Smith JW . Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J Biol Chem 2008; 283: 31378–31384.

    Article  CAS  Google Scholar 

  35. Malagelada C, Ryu EJ, Biswas SC, Jackson-Lewis V, Greene LA . RTP801 is elevated in Parkinson brain substantia nigral neurons and mediates death in cellular models of Parkinson's disease by a mechanism involving mammalian target of rapamycin inactivation. J Neurosci 2006; 26: 9996–10005.

    Article  CAS  Google Scholar 

  36. Yoshida T, Mett I, Bhunia AK, Bowman J, Perez M, Zhang L et al. Rtp801, a suppressor of mTOR signaling, is an essential mediator of cigarette smoke-induced pulmonary injury and emphysema. Nat Med 2010; 16: 767–773.

    Article  CAS  Google Scholar 

  37. Sofer A, Lei K, Johannessen CM, Ellisen LW . Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005; 25: 5834–5845.

    Article  CAS  Google Scholar 

  38. Shoshani T, Faerman A, Mett I, Zelin E, Tenne T, Gorodin S et al. Identification of a novel hypoxia-inducible factor 1-responsive gene, RTP801, involved in apoptosis. Mol Cell Biol 2002; 22: 2283–2293.

    Article  CAS  Google Scholar 

  39. Jin HO, Seo SK, Kim YS, Woo SH, Lee KH, Yi JY et al. TXNIP potentiates Redd1-induced mTOR suppression through stabilization of Redd1. Oncogene 2011; 30: 3792–3801.

    Article  CAS  Google Scholar 

  40. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004; 18: 2893–2904.

    Article  CAS  Google Scholar 

  41. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW . Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008; 22: 239–251.

    Article  CAS  Google Scholar 

  42. Pyragius CE, Fuller M, Ricciardelli C, Oehler MK . Aberrant lipid metabolism: an emerging diagnostic and therapeutic target in ovarian cancer. Int J Mol Sci 2013; 14: 7742–7756.

    Article  Google Scholar 

  43. Tania M, Khan MA, Song Y . Association of lipid metabolism with ovarian cancer. Curr Oncol 2010; 17: 6–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bandyopadhyay S, Zhan R, Wang Y, Pai SK, Hirota S, Hosobe S et al. Mechanism of apoptosis induced by the inhibition of fatty acid synthase in breast cancer cells. Cancer Res 2006; 66: 5934–5940.

    Article  CAS  Google Scholar 

  45. Ho TS, Ho YP, Wong WY, Chi-Ming CL, Wong YS, Eng-Choon OV . Fatty acid synthase inhibitors cerulenin and C75 retard growth and induce caspase-dependent apoptosis in human melanoma A-375 cells. Biomed Pharmacother 2007; 61: 578–587.

    Article  CAS  Google Scholar 

  46. Ellisen LW, Ramsayer KD, Johannessen CM, Yang A, Beppu H, Minda K et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 2002; 10: 995–1005.

    Article  CAS  Google Scholar 

  47. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008; 8: 224–236.

    Article  CAS  Google Scholar 

  48. Yang CS, Thomenius MJ, Gan EC, Tang W, Freel CD, Merritt TJ et al. Metabolic regulation of Drosophila apoptosis through inhibitory phosphorylation of Dronc. EMBO J 2010; 29: 3196–3207.

    Article  CAS  Google Scholar 

  49. Huang NJ, Zhang L, Tang W, Chen C, Yang CS, Kornbluth S . The Trim39 ubiquitin ligase inhibits APC/CCdh1-mediated degradation of the Bax activator MOAP-1. J Cell Biol 2012; 197: 361–367.

    Article  CAS  Google Scholar 

  50. Upreti M, Chu R, Galitovskaya E, Smart SK, Chambers TC . Key role for Bak activation and Bak-Bax interaction in the apoptotic response to vinblastine. Mol Cancer Ther 2008; 7: 2224–2232.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Drs Susan Murphy and Andrew Berchuck for de-identified human ovarian cancer biopsy samples, and the members of the Kornbluth laboratory for sharing reagents and discussion. This work was supported by R01 GM080333 to SK.

Author Contributions

C-SY and SK developed the concept and wrote the manuscript. C-SY and KM designed, performed the experiments and analyzed the data with help from ACR for the BiFC assays, from N-JH for immunoprecipitation of active Bax/Bak, from BH for detection of caspase-2 phosphorylation and from LZ for qPCR.

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  1. C-S Yang

    Present address: 3Current address: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA,

  2. C-S Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    C-S Yang, K Matsuura, N-J Huang, A C Robeson, B Huang, L Zhang & S Kornbluth

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  1. C-S Yang
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Correspondence to S Kornbluth.

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Yang, CS., Matsuura, K., Huang, NJ. et al. Fatty acid synthase inhibition engages a novel caspase-2 regulatory mechanism to induce ovarian cancer cell death. Oncogene 34, 3264–3272 (2015). https://doi.org/10.1038/onc.2014.271

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