Background: Androgen deprivation results in hypoxia in prostate cancer (PCa) cells and subsequently enhances the transcriptional activity of AR leading to more aggressive tumors. Concomitant with hypoxia, a significant accumulation of lipids has been observed but its significance remains unclear. Recent data indicate that lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and apoptosis, underscoring the role of lipid as a fuel for PCa growth. Since androgen deprivation ultimately increases the activity of AR, we hypothesized that dual targeting AR and lipid catabolism axes represents an attractive therapeutic approach.
Methods: To address the role of lipid use by PCa cells we have used two experimental approaches that lead to lipid accumulation: 1- Use of clinically relevant drugs etomoxir and ranolazine: Etomoxir works by inhibiting CPT1, the rate-limiting step in fat oxidation. Ranolazine is FDA-approved for angina and blocks lipid oxidation in the mitochondria. 2- Hypoxia exposure followed by re-oxygenation to mimic the dynamics of the tumor environment and induce lipid accumulation. Enzalutamide was used by itself or in combination with etomoxir to treat PCa cells, as well as CPT1-edited cells generated in our lab. Drug effects on metabolism and AR expression were studied by growth assays, LCMS, westerns, qRTPCR, and mouse xenograft studies.
Results: CPT1 is abundant in androgen-sensitive cells and tumors. Treatment with etomoxir alone significantly decreased cell viability and AR, including the ARv7 variant. Combinatorial treatment with enzalutamide synergistically enhanced this effect on viability. Systemic treatment with ranolazine alone in nude mice bearing enzalutamide-resistant cells resulted in decreased xenograft growth over 21 days, underscoring the therapeutic potential of blocking lipid catabolism to decrease CRPC tumor growth. Lipids accumulated under hypoxia (especially arachidonic acid) were used for growth following re-oxygenation. Pharmacologic inhibition of lipid use or CPT1-knockdown significantly compromised this growth following re-oxygenation, underscoring the role of lipids in supporting aggressive growth. This was observed in sensitive and CRPC models.
Conclusions: Lipid accumulation and oxidation is a cyclical phenomenon that modulates AR content and PCa growth. Combination of fat burning inhibitors and enzalutamide may offer a novel approach to anti-AR resistance in PCa, requiring less anti-androgen for more effective therapy.
Citation Format: Isabel R. Schlaepfer, Gagan Deep, Rajesh Agarwal, Zhiyong Zhang, Maren Salzmann-Sullivan, Lih-Jen Su, Thomas Flaig. CPT1A-mediated lipid catabolism modulates growth, AR expression and hypoxia survival of prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1055.