Graduate Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 35, Xiao-dong Rd, Tainan 704, Taiwan.
Carcinogenesis. 2012 Nov;33(11):2065-75. doi: 10.1093/carcin/bgs253. Epub 2012 Jul 30.
Growing evidence suggests that Stat3 contributes to chemoresistance. However, the impact of chemotherapy on Stat3 activity is unclear. We found that paclitaxel activated Stat3 in the human lung cancer cell lines PC14PE6AS2 (AS2) and H157, whereas it reduced Stat3 activation in A549 and H460 cells. Pretreatment of AS2 and H157 cells with rotenone, an inhibitor of mitochondrially produced reactive oxygen species (ROS), or carbonyl cyanide p-(trifluoromethoxy)-phenylhydrazone (FCCP), a mitochondrial uncoupler, suppressed the paclitaxel-induced activation of Stat3. Uncoupling protein 2 (UCP-2), located in the inner membrane of the mitochondria, can reduce ROS production in conditions of oxidative stress. UCP-2 protein expression in the four cancer cell lines was higher than that in normal lung epithelial cells (NL-20), but its expression was lower in AS2 and H157 cells relative to A549 and H460 cells. Silencing high UCP-2 expression with small interfering RNA (siRNA) in A549 and H460 cells restored paclitaxel-induced Stat3 activation. In addition, paclitaxel-induced Stat3 activation led to the upregulation of survivin and Mcl-1, which in turn facilitated cell survival. Moreover, the CL1-5 subline had lower UCP-2 expression relative to the parental CL1-0 cells. Treatment with paclitaxel activated Stat3 in CL1-5 but not in CL1-0 cells, whereas in CL1-5 cells, the overexpression of UCP-2 with complementary DNA (cDNA) blocked Stat3 activation. In lung cancer patients, low UCP-2 expression in cancer cells was a predictor of a poor response to chemotherapy. Therefore, UCP-2 modulates the ROS/Stat3 signaling pathway and response to chemotherapy treatment in lung cancer cells. Targeting UCP-2, ROS and Stat3 pathways may improve anticancer therapies.
越来越多的证据表明 Stat3 有助于化疗耐药。然而，化疗对 Stat3 活性的影响尚不清楚。我们发现紫杉醇激活了人肺癌细胞系 PC14PE6AS2（AS2）和 H157 中的 Stat3，但在 A549 和 H460 细胞中降低了 Stat3 的激活。用线粒体产生的活性氧（ROS）抑制剂鱼藤酮或线粒体解偶联剂羰基氰化物 p-（三氟甲氧基）-苯腙（FCCP）预处理 AS2 和 H157 细胞，可抑制紫杉醇诱导的 Stat3 激活。位于线粒体内膜的解偶联蛋白 2（UCP-2）可在氧化应激条件下减少 ROS 的产生。四种癌细胞系中的 UCP-2 蛋白表达高于正常肺上皮细胞（NL-20），但与 A549 和 H460 细胞相比，AS2 和 H157 细胞中的表达较低。用小干扰 RNA（siRNA）沉默 A549 和 H460 细胞中的高 UCP-2 表达可恢复紫杉醇诱导的 Stat3 激活。此外，紫杉醇诱导的 Stat3 激活导致凋亡抑制蛋白 survivin 和 Mcl-1 的上调，从而促进细胞存活。此外，CL1-5 亚系的 UCP-2 表达低于亲本 CL1-0 细胞。紫杉醇处理激活了 CL1-5 中的 Stat3，但没有激活 CL1-0 细胞，而在 CL1-5 细胞中，用 cDNA 过表达 UCP-2 阻断了 Stat3 的激活。在肺癌患者中，癌细胞中 UCP-2 的低表达是对化疗反应不良的预测因子。因此，UCP-2 调节肺癌细胞中的 ROS/Stat3 信号通路和对化疗治疗的反应。靶向 UCP-2、ROS 和 Stat3 通路可能改善抗癌治疗。
