Objective: Although initially effective, androgen deprivation therapy fails to achieve an enduring remission in patients with advanced prostate cancer (PCa) and the cells maintain active androgen receptor (AR) signalling. Hence, a detailed understanding of the AR-driven downstream processes that are required for tumour cell growth and survival, such as lipid metabolism, is essential to reveal new therapeutic targets. In this study, we aimed to evaluate the effect of androgens on the lipid profile of PCa cells, investigate the AR-dependent downstream pathways that mediate these changes, and evaluate their therapeutic potential as novel targets.
Methods: ESI-MS/MS-based lipidomics was used to assess lipid profiles in PCa cell lines, xenografts and patient-derived explants, and the effect of AR signalling on lipid profile. Chromatin immunoprecipitation (ChIP) and RT-PCR were used to validate AR regulation of key lipidomic enzymes, and their expression was modulated by siRNA and shRNA targeting. Tumour growth (orthotopic and subcutaneous) and metastasis was assessed in vivo using NOD/SCID mice.
Results: A complexity of changes in phospholipid profiles in response to androgen treatment was revealed. A consistent phenomenon of lipid elongation was observed for multiple phospholipid classes in response to androgen treatment, which was reversed by the antiandrogen, enzalutamide. Importantly, elongation of fatty acyl chains was also evident in clinical prostate tumors compared to non-malignant tissues. Potent and direct AR regulation of three enzymes that catalyze elongation (Elongation of Very Long Chain Fatty Acids) ELOVL2, 5 and 7 was demonstrated in prostate cancer cells, xenografts and clinical specimens. Targeting ELOVL5 (the most abundant ELOVL in clinical PCa) by siRNA or shRNA reversed the androgen-induced elongation phenotype, and significantly attenuated prostate cancer cell viability, adhesion, migration, 3D growth and in vivo tumor growth and metastasis.
Conclusions: These findings identify acyl chain elongation as a novel AR-regulated process, and an exciting new therapeutic target for prostate cancer.
17 Mar 2019 - 20 Mar 2019