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Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis
Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386908/ https://www.ncbi.nlm.nih.gov/pubmed/32686647 http://dx.doi.org/10.7554/eLife.54166 |
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author | Nassar, Zeyad D Mah, Chui Yan Dehairs, Jonas Burvenich, Ingrid JG Irani, Swati Centenera, Margaret M Helm, Madison Shrestha, Raj K Moldovan, Max Don, Anthony S Holst, Jeff Scott, Andrew M Horvath, Lisa G Lynn, David J Selth, Luke A Hoy, Andrew J Swinnen, Johannes V Butler, Lisa M |
author_facet | Nassar, Zeyad D Mah, Chui Yan Dehairs, Jonas Burvenich, Ingrid JG Irani, Swati Centenera, Margaret M Helm, Madison Shrestha, Raj K Moldovan, Max Don, Anthony S Holst, Jeff Scott, Andrew M Horvath, Lisa G Lynn, David J Selth, Luke A Hoy, Andrew J Swinnen, Johannes V Butler, Lisa M |
author_sort | Nassar, Zeyad D |
collection | PubMed |
description | Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells. |
format | Online Article Text |
id | pubmed-7386908 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-73869082020-07-29 Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis Nassar, Zeyad D Mah, Chui Yan Dehairs, Jonas Burvenich, Ingrid JG Irani, Swati Centenera, Margaret M Helm, Madison Shrestha, Raj K Moldovan, Max Don, Anthony S Holst, Jeff Scott, Andrew M Horvath, Lisa G Lynn, David J Selth, Luke A Hoy, Andrew J Swinnen, Johannes V Butler, Lisa M eLife Cancer Biology Fatty acid β-oxidation (FAO) is the main bioenergetic pathway in human prostate cancer (PCa) and a promising novel therapeutic vulnerability. Here we demonstrate therapeutic efficacy of targeting FAO in clinical prostate tumors cultured ex vivo, and identify DECR1, encoding the rate-limiting enzyme for oxidation of polyunsaturated fatty acids (PUFAs), as robustly overexpressed in PCa tissues and associated with shorter relapse-free survival. DECR1 is a negatively-regulated androgen receptor (AR) target gene and, therefore, may promote PCa cell survival and resistance to AR targeting therapeutics. DECR1 knockdown selectively inhibited β-oxidation of PUFAs, inhibited proliferation and migration of PCa cells, including treatment resistant lines, and suppressed tumor cell proliferation and metastasis in mouse xenograft models. Mechanistically, targeting of DECR1 caused cellular accumulation of PUFAs, enhanced mitochondrial oxidative stress and lipid peroxidation, and induced ferroptosis. These findings implicate PUFA oxidation via DECR1 as an unexplored facet of FAO that promotes survival of PCa cells. eLife Sciences Publications, Ltd 2020-07-20 /pmc/articles/PMC7386908/ /pubmed/32686647 http://dx.doi.org/10.7554/eLife.54166 Text en © 2020, Nassar et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cancer Biology Nassar, Zeyad D Mah, Chui Yan Dehairs, Jonas Burvenich, Ingrid JG Irani, Swati Centenera, Margaret M Helm, Madison Shrestha, Raj K Moldovan, Max Don, Anthony S Holst, Jeff Scott, Andrew M Horvath, Lisa G Lynn, David J Selth, Luke A Hoy, Andrew J Swinnen, Johannes V Butler, Lisa M Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title | Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title_full | Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title_fullStr | Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title_full_unstemmed | Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title_short | Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis |
title_sort | human decr1 is an androgen-repressed survival factor that regulates pufa oxidation to protect prostate tumor cells from ferroptosis |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386908/ https://www.ncbi.nlm.nih.gov/pubmed/32686647 http://dx.doi.org/10.7554/eLife.54166 |
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