期刊
CELL CYCLE
卷 12, 期 2, 页码 289-301出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cc.23109
关键词
ethanol; alcohol consumption; reactive oxygen species (ROS); myofibroblast; oxidative stress; ketone bodies; oxidative phosphorylation (OXPHOS); mitochondrial biogenesis; cancer metabolism; breast cancer prevention; caveolin-1; MCT4
类别
资金
- Young Investigator Award from the Breast Cancer Alliance
- Margaret Q. Landenberger Research Foundation
- National Institute on Alcohol Abuse and Alcoholism (NIAAA) [T32 AA007467]
- Centre grant in Manchester from Breakthrough Breast Cancer in the UK
- European Research Council
- Breast Cancer Now [MAN-Q1] Funding Source: researchfish
Little is known about how alcohol consumption promotes the onset of human breast cancer(s). One hypothesis is that ethanol induces metabolic changes in the tumor microenvironment, which then enhances epithelial tumor growth. To experimentally test this hypothesis, we used a co-culture system consisting of human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts. Here, we show that ethanol treatment (100 mM) promotes ROS production and oxidative stress in cancer-associated fibroblasts, which is sufficient to induce myofibroblastic differentiation. Oxidative stress in stromal fibroblasts also results in the onset of autophagy/mitophagy, driving the induction of ketone body production in the tumor microenvironment. Interestingly, ethanol has just the opposite effect in epithelial cancer cells, where it confers autophagy resistance, elevates mitochondrial biogenesis and induces key enzymes associated with ketone re-utilization (ACAT1/OXCT1). During co-culture, ethanol treatment also converts MCF7 cells from an ER(+) to an ER(-) status, which is thought to be associated with stemness, more aggressive behavior and a worse prognosis. Thus, ethanol treatment induces ketone production in cancer-associated fibroblasts and ketone re-utilization in epithelial cancer cells, fueling tumor cell growth via oxidative mitochondrial metabolism (OXPHOS). This two-compartment metabolic model is consistent with previous historical observations that ethanol is first converted to acetaldehyde (which induces oxidative stress) and then ultimately to acetyl-CoA (a high-energy mitochondrial fuel), or can be used to synthesize ketone bodies. As such, our results provide a novel mechanism by which alcohol consumption could metabolically convert low-risk breast cancer patients to high-risk status, explaining tumor recurrence or disease progression. Hence, our findings have clear implications for both breast cancer prevention and therapy. Remarkably, our results also show that antioxidants [such as N-acetyl cysteine (NAC)] can effectively reverse or prevent ethanol-induced oxidative stress in cancer-associated fibroblasts, suggesting a novel strategy for cancer prevention. We also show that caveolin-1 and MCT4 protein expression can be effectively used as new biomarkers to monitor oxidative stress induced by ethanol.
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