Long-term Nicotine Exposure-Induced Chemoresistance Is Mediated by Activation of Stat3 and Downregulation of ERK1/2 via nAChR and Beta-Adrenoceptors in Human Bladder Cancer Cells
Long-term Nicotine Exposure-Induced Chemoresistance Is Mediated by Activation of Stat3 and Downregulation of ERK1/2 via nAChR and Beta-Adrenoceptors in Human Bladder Cancer Cells
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DOI：
10.1093/toxsci/kfq028
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发表时间：
2010-05-01
影响因子：
3.8
通讯作者：
Wang, Ying-Jan
中科院分区：
文献类型：
--
作者：
Chen, Rong-Jane;Ho, Yuan-Soon;Wang, Ying-Jan
Previous reports suggested that bladder cancer patients who continue to smoke while receiving chemotherapy have poorer outcomes than their nonsmoking counterparts. Nicotine, the major addictive compound in cigarette smoke, is known to induce chemoresistance in some cancer cells. Chemoresistance has been linked to the activation of Stat3 (signal transducer and activator of transcription). The objective of this study was to identify the role of Stat3 in chemoresistance induced by nicotine in human bladder cancer cell line, T24 cells. Chemoresistant T24 cells were established by persistent nicotine treatment. Apoptosis and cell cycle parameters were analyzed by Annexin V staining, poly(ADP-ribose) polymerase degradation, caspase activity, and propidium iodide staining. Signal transduction mediating the chemoresistance was detected by Western blotting and small interfering RNA (siRNA) transfection. We provide evidence for the first time that nicotine strongly activated Stat3, leading to Cyclin D1 overexpression, cell cycle perturbations, and chemoresistance. Furthermore, nicotine mobilized Stat3 signaling, resulting in the loss of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) activation and reduced chemosensitivity via nicotinic acetylcholine receptors and beta-adrenoceptors. Inhibition of Stat3 by siRNA or a specific inhibitor restored chemosensitivity in T24 cells. Stat3 could be the major target for increasing chemosensitivity in patients who develop chemoresistance during chemotherapy, and avoidance of cigarette smoking or nicotine-based treatments may increase the efficacy of chemotherapy.
