Department of Oncology, Zhongnan Hospital, Wuhan University, Hubei Cancer Clinical Study Center, Hubei Key Laboratory of Tumor Biological Behaviors, Wuhan, Hubei 430071, P.R. China.
Int J Mol Med. 2012 May;29(5):906-12. doi: 10.3892/ijmm.2012.901. Epub 2012 Feb 3.
Recent studies have shown that transforming growth factor-β1 (TGF-β1) signaling plays important roles in the redox system in benign and malignant cells. Whether TGF-β mediates an antioxidative damage response in colorectal cancer cells is largely unknown. Herein, using the human colorectal cancer cell lines we found that TGF-β1 induced glutathione peroxidase-1 (GPx-1) expression and enzyme activity, and that the upregulation of GPx-1 by TGF-β1 could protect colorectal cell lines from H2O2-induced oxidation damage. Further, we used loss- and gain-function approaches to elucidate the underlying mechanism and found that TGF-β1 induced GPx-1 through activation of the TGF-β receptor type I (TGF-βRI)/Smad2/extracellular-signal-regulated kinase 1/2 (ERK1/2)/hypoxia-inducible factor-1α (HIF-1α) signaling pathway. This cascade could be blocked by the TGF-βRI inhibitor or ERK1/2 inhibitor. Taken together, our data demonstrated that TGF-β1 induced GPx-1 expression and enzymatic activity via the TGF-βRI/Smad2/ERK1/2/HIF-1α signaling pathway, suggesting a novel antioxidative protective function of TGF-β1 in colorectal cancer cells.
最近的研究表明，转化生长因子-β1（TGF-β1）信号在良性和恶性细胞的氧化还原系统中发挥重要作用。TGF-β 是否在结直肠癌细胞中介导抗氧化损伤反应尚不清楚。在此，我们使用人结直肠癌细胞系发现，TGF-β1 诱导谷胱甘肽过氧化物酶-1（GPx-1）的表达和酶活性，TGF-β1 上调的 GPx-1 可保护结直肠细胞系免受 H2O2 诱导的氧化损伤。此外，我们采用缺失和获得功能的方法阐明了潜在的机制，发现 TGF-β1 通过激活 TGF-β 受体 I 型（TGF-βRI）/Smad2/细胞外信号调节激酶 1/2（ERK1/2）/缺氧诱导因子-1α（HIF-1α）信号通路诱导 GPx-1。该级联反应可被 TGF-βRI 抑制剂或 ERK1/2 抑制剂阻断。综上所述，我们的数据表明，TGF-β1 通过 TGF-βRI/Smad2/ERK1/2/HIF-1α 信号通路诱导 GPx-1 的表达和酶活性，提示 TGF-β1 在结直肠癌细胞中具有新的抗氧化保护功能。
