title: Increased chemoresistance via Snail-Raf kinase inhibitor protein signaling in colorectal cancer in response to a nicotine derivative.
abstract: A tobacco-specific component, 4-methylnitrosamino-1-3-pyridyl-1-butanone (NNK), is a major risk factor for many cancers. Recent reports have demonstrated that NNK exposure may be associated with tumor progression and chemoresistance in certain cancers. However, the underlying NNK-induced mechanism contributing to the aggressiveness of colorectal cancer (CRC) has not been thoroughly studied. In this study, we used HT29 cells treated with NNK to simulate the long-term exposure of cigarette smoke. A comparative analysis was performed to evaluate cell proliferation, migration, and invasion as well as epithelial-mesenchymal transition (EMT) markers and drug-resistance genes expression, cancer stem cell (CSC) properties, and anti-apoptotic activity. Signaling pathways related to chemoresistance were also investigated. As a result, NNK exposure dose-dependently stimulates cell proliferation, enhance abilities of migration and invasion, induce EMT phenomenon, and attenuate apoptosis. Furthermore, NNK exposure also promotes the capabilities of sphere formation, upregulation of Snail, and overexpression of CD133, Nanog, OCT4, and the drug-resistant genes. Knockdown of Snail results in upregulation of Raf kinase inhibitor protein (RKIP), increased apoptosis, reversal of EMT phenomenon, and reducation of expression of CSC markers, all of which contribute to a decrease of chemoresistance. Our study demonstrates a number of related mechanisms that mediate the effect of NNK exposure on increasing CRC therapeutic resistance via the Snail signaling pathway. Targeting Snail may provide a feasible strategy for the treatment of CRC.
authors.affiliation: Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.|Division of Colon and Rectum Surgery, Department of Surgery, Tri-Service General Hospital Songshan Branch, National Defense Medical Center, Taipei, Taiwan, ROC.|Division of Colon and Rectum Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lee
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department and Graduate School of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan, ROC.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department and Graduate School of Pathology, National Defense Medical Center & Tri-Service General Hospital, Taipei, Taiwan, ROC.
authors.forename: Shin
authors.initials: S
authors.lastname: Nieh
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, ROC.
authors.forename: Yaoh-Shiang
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Division of Colon and Rectum Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC.
authors.forename: Shu-Wen
authors.initials: SW
authors.lastname: Jao
authors.affiliation: Department of Dental Hygiene, China Medical University, Taichung, Taiwan, ROC.
authors.forename: Su-Feng
authors.initials: SF
authors.lastname: Chen
authors.affiliation: Institute of Environmental and Occupational Health Sciences, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.
authors.forename: Tsung-Yun
authors.initials: TY
authors.lastname: Liu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D009602:Nitrosamines / Q000494:pharmacology*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D049488:Phosphatidylethanolamine Binding Protein / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002273:Carcinogens; D009602:Nitrosamines; D009944:Organoplatinum Compounds; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D000071250:Snail Family Transcription Factors; D000077150:Oxaliplatin; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
keywords: NNK; Snail; chemoresistance; colorectal cancer; nicotine