ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer

SIMPLE SUMMARY: The resistance mechanism of hormonal therapy has been a long-sought-after but not-yet-understood research topic in the prostate cancer (PCa) field. Here, we provide new mechanistic insights into how long-chain fatty acid contributes to enzalutamide resistance of prostate cancer. We demonstrated that ELOLV5-mediated polyunsaturated fatty acids (PUFAs) upregulation and the lipid raft-derived activation of AKT-mTOR pathway drives the therapy resistance and neuroendocrine differentiation (NED) of prostate cancer. Thus, ELOVL5 could be a potential candidate for therapeutically targeting the therapy-resistant NE-like PCa. ABSTRACT: Prostate cancer (PCa) exhibits an elevated level of de novo lipogenesis that provides both energy and basic metabolites for its malignant development. Long-chain polyunsaturated fatty acids (PUFAs) are elongated and desaturated from palmitate but their effects on PCa progression remain largely unknown. Here, we showed that PUFAs were significantly upregulated by androgen deprivation therapy (ADT) and elevated in neuroendocrine (NE)-like PCa cells. The key enzyme of PUFA elongation, ELOVL5, was overexpressed in NE-like PCa cells as well. Furthermore, we demonstrated that knocking down ELOVL5 in enzalutamide resistant NE-like PCa cells diminished the neuroendocrine phenotypes and enzalutamide resistance, while overexpressing ELOVL5 augmented the enzalutamide resistance of PCa cells in vitro and in vivo. Mechanistically, ELOVL5-mediated PUFA elongation enhanced the lipid raft-associated AKT-mTOR signaling activation and therefore contributes to the enzalutamide resistance. These findings suggest that ELOLV5-mediated PUFA elongation may be a potential novel target for the treatment of enzalutamide resistant NE-like PCa.