ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer
The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes to more effectively target the AR-d...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Association for Cancer Research
2021
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| _version_ | 1797055614546870272 |
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| author | Centenera, MM Scott, JS Machiels, J Nassar, ZD Miller, DC Zininos, I Dehairs, J Burvenich, IJG Zadra, G Chetta, P Bango, C Evergren, E Ryan, NK Gillis, JL Mah, CY Tieu, T Hanson, AR Carelli, R Bloch, K Panagopoulos, V Waelkens, E Derua, R Williams, ED Evdokioou, A Cifuentes-Rius, A Voelcker, NH Mills, IG Tilley, WD Scott, AM Loda, M Selth, LA Swinnen, JV Butler, LM |
| author_facet | Centenera, MM Scott, JS Machiels, J Nassar, ZD Miller, DC Zininos, I Dehairs, J Burvenich, IJG Zadra, G Chetta, P Bango, C Evergren, E Ryan, NK Gillis, JL Mah, CY Tieu, T Hanson, AR Carelli, R Bloch, K Panagopoulos, V Waelkens, E Derua, R Williams, ED Evdokioou, A Cifuentes-Rius, A Voelcker, NH Mills, IG Tilley, WD Scott, AM Loda, M Selth, LA Swinnen, JV Butler, LM |
| author_sort | Centenera, MM |
| collection | OXFORD |
| description | The androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes 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, yet the relationship between AR and the lipidome remain undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated 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 and upregulated in prostate cancer compared to non-malignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 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 proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a pro-tumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. |
| first_indexed | 2024-03-06T19:12:27Z |
| format | Journal article |
| id | oxford-uuid:17331f11-0a3d-4317-b2b4-d459ad39a413 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T19:12:27Z |
| publishDate | 2021 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | oxford-uuid:17331f11-0a3d-4317-b2b4-d459ad39a4132022-03-26T10:36:00ZELOVL5 is a critical and targetable fatty acid elongase in prostate cancerJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:17331f11-0a3d-4317-b2b4-d459ad39a413EnglishSymplectic ElementsAmerican Association for Cancer Research2021Centenera, MMScott, JSMachiels, JNassar, ZDMiller, DCZininos, IDehairs, JBurvenich, IJGZadra, GChetta, PBango, CEvergren, ERyan, NKGillis, JLMah, CYTieu, THanson, ARCarelli, RBloch, KPanagopoulos, VWaelkens, EDerua, RWilliams, EDEvdokioou, ACifuentes-Rius, AVoelcker, NHMills, IGTilley, WDScott, AMLoda, MSelth, LASwinnen, JVButler, LMThe androgen receptor (AR) is the key oncogenic driver of prostate cancer, and despite implementation of novel AR targeting therapies, outcomes for metastatic disease remain dismal. There is an urgent need to better understand androgen-regulated cellular processes 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, yet the relationship between AR and the lipidome remain undefined. Using mass spectrometry-based lipidomics, this study reveals increased fatty acyl chain length in phospholipids from prostate cancer cells and patient-derived explants as one of the most striking androgen-regulated 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 and upregulated in prostate cancer compared to non-malignant prostate. ELOVL5 depletion markedly altered mitochondrial morphology and function, leading to excess generation of reactive oxygen species and resulting in suppression of prostate cancer cell proliferation, 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 proliferation and migration effects of ELOVL5 knockdown. Collectively, these results identify lipid elongation as a pro-tumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. |
| spellingShingle | Centenera, MM Scott, JS Machiels, J Nassar, ZD Miller, DC Zininos, I Dehairs, J Burvenich, IJG Zadra, G Chetta, P Bango, C Evergren, E Ryan, NK Gillis, JL Mah, CY Tieu, T Hanson, AR Carelli, R Bloch, K Panagopoulos, V Waelkens, E Derua, R Williams, ED Evdokioou, A Cifuentes-Rius, A Voelcker, NH Mills, IG Tilley, WD Scott, AM Loda, M Selth, LA Swinnen, JV Butler, LM ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title | ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title_full | ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title_fullStr | ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title_full_unstemmed | ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title_short | ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer |
| title_sort | elovl5 is a critical and targetable fatty acid elongase in prostate cancer |
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