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ACSM1 and ACSM3 Regulate Fatty Acid Metabolism to Support Prostate Cancer Growth and Constrain Ferroptosis.

Authors :
Shrestha RK
Nassar ZD
Hanson AR
Iggo R
Townley SL
Dehairs J
Mah CY
Helm M
Alizadeh-Ghodsi M
Pickering M
Ghesquière B
Watt MJ
Quek LE
Hoy AJ
Tilley WD
Swinnen JV
Butler LM
Selth LA
Source :
Cancer research [Cancer Res] 2024 Jul 15; Vol. 84 (14), pp. 2313-2332.
Publication Year :
2024

Abstract

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared with nonmalignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, whereas silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation, and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function of medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance. Significance: Androgen receptor-induced ACSM1 and ACSM3 mediate a metabolic pathway in prostate cancer that enables the utilization of medium chain fatty acids for energy production, blocks ferroptosis, and drives resistance to clinically approved antiandrogens.<br /> (©2024 American Association for Cancer Research.)

Details

Language :
English
ISSN :
1538-7445
Volume :
84
Issue :
14
Database :
MEDLINE
Journal :
Cancer research
Publication Type :
Academic Journal
Accession number :
38657108
Full Text :
https://doi.org/10.1158/0008-5472.CAN-23-1489