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Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells
Zeyad D Nassar1,2, Chui Yan Mah1,2, Jonas Dehairs3
1University of Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, Australia.
Abstract:
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.
Insights
Targeting DECR1, an enzyme crucial for fatty acid beta-oxidation (FAO) in prostate cancer (PCa), shows therapeutic promise. Inhibiting DECR1 hinders PCa cell growth and metastasis, offering a new strategy against this disease.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Fatty acid beta-oxidation (FAO) is a key energy pathway in prostate cancer (PCa).
- Targeting FAO presents a potential therapeutic strategy for PCa.
- DECR1, a rate-limiting enzyme in polyunsaturated fatty acid (PUFA) oxidation, is implicated in PCa progression.
Purpose of the Study:
- To investigate the therapeutic efficacy of targeting FAO in prostate tumors.
- To identify DECR1 as a potential therapeutic target in PCa.
- To elucidate the role of DECR1 in PCa cell survival and resistance to therapy.
Main Methods:
- Ex vivo culture of clinical prostate tumors to assess FAO targeting efficacy.
- Gene expression analysis to identify DECR1 overexpression in PCa tissues.
- DECR1 knockdown experiments in PCa cell lines and mouse xenograft models.
- Analysis of PUFA accumulation, oxidative stress, lipid peroxidation, and ferroptosis.
Main Results:
- DECR1 is overexpressed in PCa tissues and linked to shorter relapse-free survival.
- DECR1 knockdown selectively inhibited PUFA oxidation, PCa cell proliferation, and migration.
- DECR1 targeting suppressed tumor growth and metastasis in vivo.
- DECR1 inhibition led to PUFA accumulation, oxidative stress, lipid peroxidation, and ferroptosis.
Conclusions:
- DECR1 is a critical enzyme in PUFA oxidation and promotes PCa cell survival.
- DECR1 is a promising therapeutic target for prostate cancer, including treatment-resistant forms.
- Targeting DECR1-mediated PUFA oxidation offers a novel strategy to combat PCa.
