Abstract 6039: ELOVL5 affects prostate cancer cell proliferation and modulates the AR pathway

Abstract Prostate cancer (PCa) is characterized by alterations in lipid metabolism, exemplified by increased rates of de novo lipogenesis and elongation by fatty acid elongase enzymes known as ELOVLs (elongation of very long chain fatty acids). We have previously shown that the ELOVL family members ELOVL2, 5, and 7 are Androgen Receptor (AR)-regulated proteins; and that ELOVL5 is overexpressed in both primary and castration-resistant prostate cancer. To confirm the role of ELOVL5 activity in prostate carcinogenesis, we generated genetically engineered mouse models (GEMM) with deletion of Elovl5, validated by immunohistochemistry, in combination with the overexpression of c-Myc, an oncogene known to affect lipid metabolism in cancer cells. As expected, we observed alterations in the lipid profile of the murine prostate with the partial deletion of Elovl5, as determined by a significant reduction in levels of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) with long-chain fatty acids (22 carbons) and increased levels of PE with short-chain fatty acids (14 carbons), suggesting an overall shortening on acyl chains of the most common phospholipid species. Interestingly, we also observed that the heterozygous deletion of Elovl5 reduced the expression levels of the AR on the anterior lobe of the murine prostate, in comparison to tissue from Elovl5 wild type mice. Preliminary data also indicates a modulation in prostate volume when Elovl5 is genetically deleted in comparison to tissue from wild type mice. Heterozygous Elovl5 deletion did not affect healthy tissue.To explore biological effects, we generated a 3D organoid line derived from the prostate of mice with homozygous deletion of Elovl5 and overexpression of c-Myc. We found that Elovl5 knock-out decreased organoid diameter and proliferation of c-Myc-driven cells compared to Elovl5 WT. This effect was potentiated when organoids were treated with Enzalutamide, suggesting that targeting Elovl5 may sensitize prostate cells to anti-androgen therapy.Our findings suggest lipid elongation via ELOVL5 as a potential therapeutic target for PCa. Citation Format: Silvia D. Rodrigues, Caroline Ribeiro, Isadora Teixeira, Hubert Pakula, Giuseppe N. Fanelli, Fabio Socciarelli, Lisa Butler, Johannes Swinnen, Massimo Loda. ELOVL5 affects prostate cancer cell proliferation and modulates the AR pathway. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6039.