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

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.

• Authors: Joseph Longo, Peter J Mullen, Rosemary Yu, Jenna E van Leeuwen, Mehdi Masoomian, Dixon T S Woon, Yuzhuo Wang, Eric X Chen, Robert J Hamilton, Joan M Sweet, Theodorus H van der Kwast, Neil E Fleshner, Linda Z Penn
• Journal: Molecular metabolism (Mol Metab) Vol. 25 Pg. 119-130 (07 2019) ISSN: 2212-8778 [Electronic] Germany
• PMID: 31023626 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 University Health Network. Published by Elsevier GmbH.. All rights reserved.

Chemical References

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

Topics

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