Tang Shifu, Hou Yixuan, Zhang Hailong, Tu Gang, Yang Li, Sun Yifan, Lang Lei, Tang Xi, Du Yan-E, Zhou Mingli, Yu Tenghua, Xu Liyun, Wen Siyang, Liu Chunming, Liu Manran
a Key Laboratory of Laboratory Medical Diagnostics; Chinese Ministry of Education; Chongqing Medical University ; Chongqing , China.
Cell Cycle. 2015;14(12):1908-24. doi: 10.1080/15384101.2015.1041685.
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 β-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.
异常增殖是癌症相关成纤维细胞（CAFs）的一个特征，其在肿瘤发生和肿瘤进展中起关键作用。氧化应激（OS）是CAFs异常增殖的根本原因。ATM（共济失调毛细血管扩张突变蛋白激酶）作为一种重要的氧化还原传感器，参与DNA损伤反应和细胞内稳态。氧化型ATM是否以及如何调节CAFs增殖仍不清楚。在本研究中，我们发现乳腺癌CAFs中在不存在双链断裂（DSBs）的情况下存在高水平的氧化型ATM，并且氧化型ATM在CAFs增殖中起关键作用。氧化型ATM对CAFs增殖的影响是通过其对细胞氧化还原平衡以及ERK、PI3K-AKT和Wnt信号通路活性的调节来介导的。用抗氧化剂N-乙酰半胱氨酸（NAC）处理细胞可部分挽救由ATM缺陷引起的乳腺癌CAFs的增殖缺陷。用ERK、PI3K-AKT和Wnt信号通路的特异性抑制剂单独或联合处理细胞可模拟ATM缺陷对乳腺癌CAF增殖的影响。这主要归因于β-连环蛋白的抑制和c-Myc的下调，从而进一步导致细胞周期蛋白D1、细胞周期蛋白E和E2F1表达降低以及p21（Cip1）水平升高。我们的结果揭示了氧化型ATM在调节乳腺癌CAFs异常增殖中的重要作用。氧化型ATM可作为治疗乳腺癌的潜在靶点。
