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

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Journal:

Molecular Metabolism

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

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 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.

DOI: https://doi.org/10.1016/j.molmet.2019.04.003