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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-07-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/54166 |
| id |
doaj-691410c791b2452584ed62099c163640 |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Zeyad D Nassar Chui Yan Mah Jonas Dehairs Ingrid JG Burvenich Swati Irani Margaret M Centenera Madison Helm Raj K Shrestha Max Moldovan Anthony S Don Jeff Holst Andrew M Scott Lisa G Horvath David J Lynn Luke A Selth Andrew J Hoy Johannes V Swinnen Lisa M Butler |
| spellingShingle |
Zeyad D Nassar Chui Yan Mah Jonas Dehairs Ingrid JG Burvenich Swati Irani Margaret M Centenera Madison Helm Raj K Shrestha Max Moldovan Anthony S Don Jeff Holst Andrew M Scott Lisa G Horvath David J Lynn Luke A Selth Andrew J Hoy Johannes V Swinnen Lisa M Butler Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis eLife lipid metabolism prostate cancer ferroptosis androgen |
| author_facet |
Zeyad D Nassar Chui Yan Mah Jonas Dehairs Ingrid JG Burvenich Swati Irani Margaret M Centenera Madison Helm Raj K Shrestha Max Moldovan Anthony S Don Jeff Holst Andrew M Scott Lisa G Horvath David J Lynn Luke A Selth Andrew J Hoy Johannes V Swinnen Lisa M Butler |
| author_sort |
Zeyad D Nassar |
| title |
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_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_sort |
human decr1 is an androgen-repressed survival factor that regulates pufa oxidation to protect prostate tumor cells from ferroptosis |
| publisher |
eLife Sciences Publications Ltd |
| series |
eLife |
| issn |
2050-084X |
| publishDate |
2020-07-01 |
| 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. |
| topic |
lipid metabolism prostate cancer ferroptosis androgen |
| url |
https://elifesciences.org/articles/54166 |
| work_keys_str_mv |
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1721458253740638208 |
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doaj-691410c791b2452584ed62099c1636402021-05-05T21:19:20ZengeLife Sciences Publications LtdeLife2050-084X2020-07-01910.7554/eLife.54166Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosisZeyad D Nassar0https://orcid.org/0000-0002-7779-2697Chui Yan Mah1https://orcid.org/0000-0002-8820-4037Jonas Dehairs2Ingrid JG Burvenich3Swati Irani4Margaret M Centenera5Madison Helm6Raj K Shrestha7Max Moldovan8Anthony S Don9Jeff Holst10Andrew M Scott11Lisa G Horvath12David J Lynn13Luke A Selth14Andrew J Hoy15Johannes V Swinnen16Lisa M Butler17https://orcid.org/0000-0003-2698-3220University of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaKU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, BelgiumTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, AustraliaUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaDame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, AustraliaSouth Australian Health and Medical Research Institute, Adelaide, AustraliaNHMRC Clinical Trials Centre, and Centenary Institute, The University of Sydney, Camperdown, AustraliaTranslational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW Sydney, Sydney, AustraliaTumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Melbourne, AustraliaGarvan Institute of Medical Research, NSW 2010; University of Sydney, NSW 2006; and University of New South Wales, Darlinghurst, AustraliaSouth Australian Health and Medical Research Institute, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, AustraliaUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide, Adelaide, Australia; College of Medicine and Public Health, Flinders University, Bedford Park, AustraliaDiscipline of Physiology, School of Medical Sciences, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, AustraliaKU Leuven- University of Leuven, LKI- Leuven Cancer Institute, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, Leuven, BelgiumUniversity of Adelaide Medical School and Freemasons Foundation Centre for Men’s Health, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, AustraliaFatty 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.https://elifesciences.org/articles/54166lipid metabolismprostate cancerferroptosisandrogen |