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

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

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada.
3
Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, Ontario, M5G 2C4, Canada.
4
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
5
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada; Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, V5Z 1L3, Canada.
6
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada. Electronic address: lpenn@uhnresearch.ca.

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

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