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

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.

ELOVL5‐mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma

“…50 , 51 This was demonstrated by Rueda‐Rincin et al and Xu et al who tied oleic acid (OA) and AA administration to increased AKT phosphorylation. 34 , 51 Our results are in line with these reports indicating that MUFA and PUFA are important FA in AKT phosphorylation. Future studies into direct binding assays will reveal any potential synergy between stearoyl‐CoA desaturases and the ELOVL family of chain elongators.…”

Fatty Acid Metabolism Reprogramming in Advanced Prostate Cancer

“…However, in our previous research [24], we did not find that FA oxidation was enhanced in CRPC-NEPC cell lines. Instead, the source of oxidation mainly depends on the FA present in the medium.…”

“…As is reported for PC3 cells, which is a small cell PCa cell line, docosahexaenoic acid and eicosapentanoic acid show inhibitory effects on the uptake of phosphatidic acid and arachidonic acid [102]. In our previous study, we did not find that NEPC cells benefitted from the uptake of palmitate and oleic acid while arachidonic acid, a kind of PUFA, contributed to the activation of the AKT-mTOR pathway, inducing the neuroendocrine switch and enzalutamide resistance [24].…”

“…Work by Centenera et al identified ELOVL5 as a pro-tumorigenic metabolic factor in PCa that is androgen-regulated and is critical for metastasis and PCa growth [122]. Intriguingly, according to our own research [24], FA elongation is enhanced after prolonged androgen deprivation therapy and in advanced PCa, including neuroendocrine PCa (NEPC). With additional arachidonic Acid (AA), one of the main PUFA, in the cell culture medium, prostate cancer cell lines present more enzalutamide resistance.…”

“…Other specific nutrients that may impact PCa include ω3 and ω6 polyunsaturated fatty acids (PUFA), which cannot be synthesized de novo, and must be taken in from food [22]. Research has suggested that the consumption of the ω3 PUFA arachidonic acid promotes the development of PCa, while eicosapentanoic acid and docosahexanoic acid might have protective effects [23,24].…”