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Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer, "Beyond the Abstract," by Warren A. Chow, MD, FACP

BERKELEY, CA (UroToday.com) - Nelfinavir, an HIV protease inhibitor, has pleiotropic effects in cancer cells, including downregulation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, inhibition of signal transducer and activator of transcription factor 3 (STAT3) signaling, downregulation of the androgen receptor (AR) and blockade of AR signaling, inhibition of cyclin-dependent kinase 2 (CDK2) function, and induction of malignant cell death by inducing endoplasmic reticulum (ER) stress.[1,2,3,4,5,6,7] Recently, using a chemical systems biology approach, weak inhibition of multiple kinases was found to contribute to its anticancer effect.[8] These reports have stimulated interest in repositioning it as an anticancer agent.[9]

bta chowThe current report adds to the expanding list of potential mechanisms for its anticancer effect.[10] We report that nelfinavir inhibits regulated intramembrane proteolysis (RIP) by selectively inhibiting site-2 protease (S2P). RIP is an evolutionarily conserved, necessary process, that produces mature transcription factors such as sterol regulatory element binding protein-1 (SREBP-1) and activating transcription factor 6 (ATF6) from their inactive, precursor forms. SREBP-1 is the “master” transcription factor regulating lipogenesis, and ATF6 mediates the unfolded protein response (UPR).[11] Most secreted and transmembrane proteins fold and mature in the endoplasmic reticulum (ER) before transportation.[12] Cells respond to ER protein misfolding (ER stress) by activating the UPR. When the UPR capacity is exceeded, apoptosis is triggered.[12]

Importantly, androgens stimulate lipogenesis and lipid accumulation in androgen-dependent prostate cancer cells, and SREBP-1 is upregulated in castration-resistant prostate cancer (CRPC).[13,14] This is consistent with CRPC developing a lesser-known hallmark of cancer, the “lipogenic phenotype.” Here, increased de novo synthesis of fatty acid (FA) occurs.[15] FAs are used by proliferating cancer cells to produce lipids for membrane synthesis, energy production, and lipid-based protein modification. Notably, a downstream target of SREBP-1, fatty acid synthase (FAS), which converts malonyl-CoA to long-chain fatty acids (FA), is a promising target for cancer therapeutics.[16]

Because ATF6 regulates UPR and SREBP-1 regulates lipogenesis, interruption of their proteolytic processing should induce ER stress and inhibit the “lipogenic phenotype.” Indeed, this report demonstrates that nelfinavir inhibits nuclear translocation of ATF6 and SREBP-1 in CRPC through inhibition of S2P, resulting in reduced proliferation and increased apoptosis (10). Small interfering RNAs (siRNAs) targeting S2P recapitulate the nelfinavir-treated phenotype and 1,10 phenanthroline, an S2P inhibitor, also reproduces this phenotype. Additionally, inhibition of nelfinavir-induced autophagy with hydoxychloroquine enhances the apoptotic effect of nelfinavir. This is the first report to demonstrate that S2P is a potential therapeutic target in CRPC.

Nelfinavir is currently being explored in a number of ongoing clinical trials.[17] We have recently reported the results of a phase I trial of nelfinavir in liposarcomas, where dosing as high as 4 250 mg twice daily was achieved with minimal toxicities.[18] For reference, the FDA-approved dose of nelfinavir in combination anti-HIV therapy is 1 250 mg twice daily.[19] Because nelfinavir was very well tolerated, future studies investigating its use alone or in combination with chemotherapy in CRPC may be warranted.

References:

  1. Yang Y, Ikezoe T, Nishioka C, et al. NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signaling, apoptosis and docetaxel sensitization in NSCLC cell lines. Br J Cancer 2006;95:1653-62.
  2. Pore N, Gupta AK, Cerniglia GJ, et al. Nelfinavir down-regulates hypoxia-inducible factor 1α and VEGF expression and increases tumor oxygenation: implications for radiotherapy. Cancer Res 2006;66:9252-9.
  3. Jiang Z, Pore N, Cerniglia GJ, et al. Phosphatase and tensin homologue deficiency in glioblastoma confers resistance to radiation and temozolomide that is reversed by the protease inhibitor nelfinavir. Cancer Res 2007;67:4467-73.
  4. Yang Y, Ikezoe T, Takeuchi T, et al. HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling. Cancer Sci 2005;96:425-33.
  5. Jiang W, Mikochik PJ, Ra JH, et al. HIV protease inhibitor nelfinavir inhibits growth of human melanoma cells by induction of cell cycle arrest. Cancer Res 2007;67:1221-7.
  6. Gills JJ, LoPiccolo J, Tsurutani J, et al. Nelfinavir, a lead HIV protease inhibitor, is a broad-spectrum, anticancer agent that induces endoplasmic reticulum stress, autophagy, and apoptosis in vitro and in vivo. Clin Cancer Res 2007;13:5183-94.
  7. Pyrko P, Kardosh A, Wang W, et al. HIV-1 protease inhibitors nelfinavir and atazanavir induce malignant glioma death by triggering endoplasmic reticulum stress. Cancer Res 2007;67:10920-8.
  8. Xie L, Evangelidis T, Xie L, et al. Drug discovery using chemical systems biology: Weak inhibition of multiple kinases may contribute to the anti-cancer effect of nelfinavir. PLoS Comput Biol 2011;7:e1002037.
  9. Chow WA, Jiang C, Guan M. Anti-HIV drugs for cancer therapeutics: back to the future? Lancet Oncol 2009;10:61-71.
  10. Guan M, Fousek K, Chow WA. Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer. FEBS J 2012;279:2399-411.
  11. Brown MS, Ye J, Rawson RB, et al. Regulated intramembrane proteolysis: a control mechanism conserved from bacteria to humans. Cell 2000;100:391-8.
  12. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 2007;8:519-29.
  13. Swinnen JV, Ulrix W, Heyns W, et al. Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci USA 1997;94:12975-80.
  14. Ettinger SL, Sobel R, Whitmore, et al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen-independence. Cancer Res 2004;64:2212-21.
  15. Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 2007;7:763-77.
  16. Mashima T, Seimiya H, Tsuruo T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 2009;100:1369-72.
  17. http://clinicaltrials.gov/ct2/results?term=nelfinavir+cancer. Accessed August 28, 2012, 2012.
  18. Pan J, Mott M, Xi B, et al. Phase I study of nelfinavir in liposarcoma. Cancer Chemother Pharmacol 2012. In press.
  19. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020778ap.pdf. Accessed July 10, 2012. 

 

Written by:

Warren A. Chow, MD, FACP as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Medical Oncology & Therapeutics Research
Department of Molecular Pharmacology
City of Hope
1500 E. Duarte Rd.
Duarte, CA USA

 

Nelfinavir inhibits regulated intramembrane proteolysis of sterol regulatory element binding protein-1 and activating transcription factor 6 in castration-resistant prostate cancer - Abstract

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