ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer
| Autor: | Wayne D. Tilley, Andrew M. Scott, Irene Zinonos, Paolo Chetta, Ryan Carelli, Zeyad D. Nassar, Jonas Dehairs, Joanna L. Gillis, Massimo Loda, Nicolas H. Voelcker, Andreas Evdokiou, Johannes V. Swinnen, Etienne Waelkens, Luke A. Selth, Vasilios Panagopoulos, Natalie K. Ryan, Chui Yan Mah, Ian G. Mills, Elizabeth D. Williams, Deanna C. Miller, Julia S. Scott, Katarzyna Bloch, Margaret M. Centenera, Lisa M. Butler, Emma Evergren, Rita Derua, Giorgia Zadra, Terence Tieu, Ingrid Burvenich, Clyde Bango, Adrienne R. Hanson, Jelle Machiels, Anna Cifuentes-Rius |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Cancer Research Fatty Acid Elongases Mice SCID Gene Expression Regulation Enzymologic Metastasis Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine SDG 3 - Good Health and Well-being Cell Movement Mice Inbred NOD Prostate Tumor Cells Cultured medicine Animals Humans Molecular Targeted Therapy RNA Small Interfering Cell Proliferation chemistry.chemical_classification Science & Technology Prostatic Neoplasms Fatty acid Lipid metabolism Lipidome Lipid Metabolism medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Androgen receptor 030104 developmental biology medicine.anatomical_structure Oncology chemistry Receptors Androgen Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer research Fatty acid elongation Life Sciences & Biomedicine |
| Zdroj: | Centenera, M M, Scott, J S, Machiels, J, Nassar, Z D, Miller, D C, Zininos, I, Dehairs, J, Burvenich, I J G, Zadra, G, Chetta, P, Bango, C, Evergren, E, Ryan, N K, Gillis, J L, Mah, C Y, Tieu, T, Hanson, A R, Carelli, R, Bloch, K, Panagopoulos, V, Waelkens, E, Derua, R, Williams, E D, Evdokioou, A, Cifuentes-Rius, A, Voelcker, N H, Mills, I G, Tilley, W D, Scott, A M, Loda, M, Selth, L A, Swinnen, J V & Butler, L M 2021, ' ELOVL5 is a critical and targetable fatty acid elongase in prostate cancer ', Cancer Research . https://doi.org/10.1158/0008-5472.CAN-20-2511 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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 remains 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 data sets revealed ELOVL5 as the predominant ELOVL expressed and upregulated in prostate cancer compared with nonmalignant 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 protumorigenic metabolic pathway in prostate cancer that is androgen-regulated, critical for metastasis, and targetable via ELOVL5. Significance: This study identifies phospholipid elongation as a new metabolic target of androgen action that is critical for prostate tumor metastasis. |
| Databáze: | OpenAIRE |
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