期刊
CELL CYCLE
卷 14, 期 12, 页码 1908-1924出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1041685
关键词
abnormal proliferation; breast cancer; cancer-associated fibroblasts; oxidized ATM; oxidative stress; proliferation signaling pathways; reactive oxygen species; redox homeostasis; CAFs; cancer associated fibroblasts; ATM; ataxia telangiectasia mutated; OS; oxidative stress; ROS; reactive oxygen species; DSBs; double strand breaks; NAC; N-acetyl-cysteine; TM; tumor microenvironment; NFs; normal fibroblasts; CDK1; cyclin-dependent kinase 1; E2F1; E2F transcription factor 1; CCNA2; cyclin A2; CCNB2; cyclin B2; CDKN2B; cyclin-dependent kinase inhibitor 2B
类别
资金
- National Natural Science Foundation of China [NSFC8147247, NSFC81402180, NSFC 31171336]
- Ministry of Education, China [20125503110001]
- Chongqing Medical University
Abnormal proliferation is one characteristic of cancer-associated fibroblasts (CAFs), which play a key role in tumorigenesis and tumor progression. Oxidative stress (OS) is the root cause of CAFs abnormal proliferation. ATM (ataxia-telangiectasia mutated protein kinase), an important redox sensor, is involved in DNA damage response and cellular homeostasis. Whether and how oxidized ATM regulating CAFs proliferation remains unclear. In this study, we show that there is a high level of oxidized ATM in breast CAFs in the absence of double-strand breaks (DSBs) and that oxidized ATM plays a critical role in CAFs proliferation. The effect of oxidized ATM on CAFs proliferation is mediated by its regulation of cellular redox balance and the activity of the ERK, PI3K-AKT, and Wnt signaling pathways. Treating cells with antioxidant N-acetyl-cysteine (NAC) partially rescues the proliferation defect of the breast CAFs caused by ATM deficiency. Administrating cells with individual or a combination of specific inhibitors of the ERK, PI3K-AKT, and Wnt signaling pathways mimics the effect of ATM deficiency on breast CAF proliferation. This is mainly ascribed to the -catenin suppression and down-regulation of c-Myc, thus further leading to the decreased cyclinD1, cyclinE, and E2F1 expression and the enhanced p21(Cip1) level. Our results reveal an important role of oxidized ATM in the regulation of the abnormal proliferation of breast CAFs. Oxidized ATM could serve as a potential target for treating breast cancer.
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