ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer

Abstract

The androgen receptor (AR) is the key oncogenic driver of prostate cancer and despite implementation of novel AR targeting therapies, patient outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen regulated cellular processes, in order to more effectively target the AR-dependence of prostate cancer cells through new therapeutic vulnerabilities. Transcriptomic studies have consistently identified lipid metabolism as a hallmark of enhanced AR signaling in prostate cancer, however the relationship between AR and the lipidome remain undefined. Using mass spectrometrybased lipidomics, this study revealed increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgenregulated changes to lipid metabolism. Potent and direct AR-mediated induction of ELOVL Fatty Acid Elongase 5 (ELOVL5), an enzyme that catalyzes fatty acid elongation, was demonstrated in prostate cancer cells, xenografts and clinical tumors. Assessment of mRNA and protein in large-scale datasets revealed ELOVL5 as the predominant ELOVL expressed in both primary and metastatic prostate cancer, and upregulated compared to non-malignant prostate. ELOVL5 depletion by siRNA markedly altered mitochondrial function to induce oxidative stress, resulting in significant inhibition of prostate cancer cell viability, 3D growth, and in vivo tumor growth and metastasis. Supplementation with the monounsaturated fatty acid cis-vaccenic acid, a direct product of ELOVL5 elongation, reversed the oxidative stress and associated cell viability caused by ELOVL5 knockdown. We have identified lipid elongation as a pro-survival metabolic pathway in prostate cancer that is androgenregulated, critical for metastasis and targetable via ELOVL5.

Isomer-Resolved Imaging of Prostate Cancer Tissues Reveals Specific Lipid Unsaturation Profiles Associated With Lymphocytes and Abnormal Prostate Epithelia

“…Therefore, the observed changes in the relative abundance of PC 34:1 n -7 and PC 34:1 n -9 within prostate tissue ( Figure 2 ) indicate a discrete difference in the ordering of desaturation and elongation reactions, and suggests region-specific aberrations in the SCD-1 and ELOVL5 and/or ELOVL6 enzyme system(s). Indeed, recent work has shown that ELOVL5 is significantly upregulated within prostate cancer and depletion of the elongase lead to the generation of reactive oxidative lipid species and hindered cancer cell growth and proliferation ( 38 ). Previous research has implicated these enzyme systems in cancer, with overexpression of SCD-1 being linked to progression and growth of hepatocellular ( 39 ), renal ( 40 ), colorectal ( 41 ) and prostate ( 42 ) cancers.…”

Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

“…Certainly a possibility is that increased quantities of intracellular fatty acids are beneficial. This is supported by experiments that show that 1) supplementation of fatty acids can rescue growth inhibition due to inhibition of fatty acid synthesis (49,54,56) and 2) inhibition of lipid uptake also inhibits prostate cancer growth (79,80). Indeed the dogma of de novo fatty acid synthesis in cancer is that it is a critical source of lipids that serve as biosynthetic building blocks for cell and organelle membrane formation for rapid proliferation.…”

“…Inhibition of the rate-limiting enzyme ACC by RNAi-mediated silencing or by soraphen A reduced proliferation of CRPC cell lines, which could be rescued by addition of palmitate to the media (52,53). Moreover, genetic knock-down of the fatty acid elongases ELOVL5 (54) or ELOVL7 (26) inhibits growth of CRPC xenograft tumors and human tumor explants. Interestingly, ELOVL5 knock-down also reduced metastasis of mouse orthotopic prostate cancer, and in vitro growth could be rescued by supplementation with cis-vaccenic acid, the fatty acid product of ELOVL5 (54).…”

“…Moreover, genetic knock-down of the fatty acid elongases ELOVL5 (54) or ELOVL7 (26) inhibits growth of CRPC xenograft tumors and human tumor explants. Interestingly, ELOVL5 knock-down also reduced metastasis of mouse orthotopic prostate cancer, and in vitro growth could be rescued by supplementation with cis-vaccenic acid, the fatty acid product of ELOVL5 (54). This study suggests that de novo fatty acid synthesis may be important for metastasis in addition to proliferation.…”

Prostate Cancer Progression: as a Matter of Fats

“…These features were rescued by the supplementation of cis-vaccenic MUFA, a direct product of ELOVL-5 elongation. These data suggest that lipid elongation is a metastasis-promoter metabolic pathway, which is targetable via ELOVL-5 (52). Aside from membrane lipid elongation, ELOVL-5 has more recently been involved in the generation of eicosanoids, inflammatory lipids with potent pro-tumorigenic signaling effects (9).…”