Long-term Nicotine Exposure-Induced Chemoresistance is Mediated by Activation of Stat3 and Downregulation of ERK1/2 via nAChR and beta-AR in Human Bladder Cancer Cells
By: Chen RJ, Ho YS, Guo HR, Wang YJ.

Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
Toxicol Sci. 2010 Jan 27.

Abstract

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 is 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, PARP degradation, caspase activity, and PI staining. Signal transduction mediating the chemoresistance was detected by Western blotting and 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 ERK1/2 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.

PMID: 20106947 [PubMed − as supplied by publisher] Source: National Library of Medicine.






* Albert Einstein College of Medicine has been
awarded Acceditation with Commendation by
the ACCME

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