title: MiR-16 targets Bcl-2 in paclitaxel-resistant lung cancer cells and overexpression of miR-16 along with miR-17 causes unprecedented sensitivity by simultaneously modulating autophagy and apoptosis.
abstract: Non-small cell lung cancer is one of the most aggressive cancers as per as the mortality and occurrence is concerned. Paclitaxel based chemotherapeutic regimes are now used as an important option for the treatment of lung cancer. However, resistance of lung cancer cells to paclitaxel continues to be a major clinical problem nowadays. Despite impressive initial clinical response, most of the patients eventually develop some degree of paclitaxel resistance in the course of treatment. Previously, utilizing miRNA arrays we reported that downregulation of miR-17 is at least partly involved in the development of paclitaxel resistance in lung cancer cells by modulating Beclin-1 expression [1]. In this study, we showed that miR-16 was also significantly downregulated in paclitaxel resistant lung cancer cells. We demonstrated that anti-apoptotic protein Bcl-2 was directly targeted miR-16 in paclitaxel resistant lung cancer cells. Moreover, in this report we showed that the combined overexpression of miR-16 and miR-17 and subsequent paclitaxel treatment greatly sensitized paclitaxel resistant lung cancer cells to paclitaxel by inducing apoptosis via caspase-3 mediated pathway. Combined overexpression of miR-16 and miR-17 greatly reduced Beclin-1 and Bcl-2 expressions respectively. Our results indicated that though miR-17 and miR-16 had no common target, both miR-16 and miR-17 jointly played roles in the development of paclitaxel resistance in lung cancer. miR-17 overexpression reduced cytoprotective autophagy by targeting Beclin-1, whereas overexpression of miR-16 potentiated paclitaxel induced apoptotic cell death by inhibiting anti-apoptotic protein Bcl-2.
authors.affiliation: Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB 700019, India.
authors.forename: Abhisek
authors.initials: A
authors.lastname: Chatterjee
authors.affiliation: Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB 700019, India.
authors.forename: Dhrubajyoti
authors.initials: D
authors.lastname: Chattopadhyay
authors.affiliation: Department of Biotechnology and Dr. B.C. Guha Centre for Genetic Engineering and Biotechnology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, WB 700019, India. Electronic address: gcbcg@caluniv.ac.in.
authors.forename: Gopal
authors.initials: G
authors.lastname: Chakrabarti
mesh_terms: D020413:3' Untranslated Regions; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D001483:Base Sequence; D000071186:Beclin-1; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C505362:MIRN16 microRNA, human; C524941:MIRN17 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D053148:Caspase 3; D017239:Paclitaxel
keywords: Apoptosis; Autophagy; Paclitaxel resistance; miR-16 and Bcl-2; miR-17 and Beclin-1