An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer

Mol Metab. 2019 Jul;25:119-130. doi: 10.1016/j.molmet.2019.04.003. Epub 2019 Apr 10.

Abstract

Objective: The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.

Methods: Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry.

Results: High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.

Conclusion: Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

Keywords: Dipyridamole; Drug repurposing; Mevalonate pathway; Prostate cancer; Statins; Tumor metabolism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dipyridamole / pharmacology
  • Drug Repositioning
  • Fluvastatin / pharmacology
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Lipid Metabolism / genetics
  • Male
  • Mevalonic Acid / metabolism*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism
  • Sterols / metabolism*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 2
  • Sterols
  • Fluvastatin
  • Dipyridamole
  • Hydroxymethylglutaryl CoA Reductases
  • Mevalonic Acid

Grant support