前列腺癌
癌症
癌症研究
脂质体
癌细胞
前列腺
脂质代谢
生物
脂质过氧化
内分泌学
内科学
氧化应激
化学
医学
作者
Raj K. Shrestha,Zeyad D. Nassar,Adrienne R. Hanson,Richard Iggo,Scott L. Townley,Jonas Dehairs,Chui Y. Mah,Madison Helm,Mohammadreza Alizadeh‐Ghodsi,Marie Pickering,Bart Ghesquière,Matthew J. Watt,Lake‐Ee Quek,Andrew J. Hoy,Wayne D. Tilley,Johannes V. Swinnen,Lisa M. Butler,Luke A. Selth
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2024-04-24
被引量:1
标识
DOI:10.1158/0008-5472.can-23-1489
摘要
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 to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, while 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 for medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.
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