miR-17-5p Downregulation Contributes to Paclitaxel Resistance of Lung Cancer Cells through Altering Beclin1 Expression

• DOI: 10.1371/journal.pone.0095716
• Publication Date: 2014-04-22T20:57:53Z
• Authors: Abhisek Chatterjee; Dhrubajyoti Chatt...; Gopal Chakrabarti
• Keywords: 0301 basic medicine; Lung Neoplasms; Science; Down-Regulation; Apoptosis; 03 medical and health sciences; Cell Line, Tumor; Autophagy; Cluster Analysis; Humans; 3' Untranslated Regions; Membrane Potential, Mitochondrial; Binding Sites; Base Sequence; Gene Expression Profiling; Q; R; Cytochromes c; Membrane Proteins; Antineoplastic Agents, Phytogenic; 3. Good health; Gene Expression Regulation, Neoplastic; MicroRNAs; Drug Resistance, Neoplasm; Medicine; Beclin-1; Apoptosis Regulatory Proteins; Research Article

Non-small-cell lung cancer (NSCLC) is one of the most leading causes of cancer-related deaths worldwide. Paclitaxel based combination therapies have long been used as a standard treatment in aggressive NSCLCs. But paclitaxel resistance has emerged as a major clinical problem in combating non-small-cell lung cancer and autophagy is one of the important mechanisms involved in this phenomenon. In this study, we used microRNA (miRNA) arrays to screen differentially expressed miRNAs between paclitaxel sensitive lung cancer cells A549 and its paclitaxel-resistant cell variant (A549-T24). We identified miR-17-5p was one of most significantly downregulated miRNAs in paclitaxel-resistant lung cancer cells compared to paclitaxel sensitive parental cells. We found that overexpression of miR-17-5p sensitized paclitaxel resistant lung cancer cells to paclitaxel induced apoptotic cell death. Moreover, in this report we demonstrated that miR-17-5p directly binds to the 3'-UTR of beclin 1 gene, one of the most important autophagy modulator. Overexpression of miR-17-5p into paclitaxel resistant lung cancer cells reduced beclin1 expression and a concordant decease in cellular autophagy. We also observed similar results in another paclitaxel resistant lung adenosquamous carcinoma cells (H596-TxR). Our results indicated that paclitaxel resistance of lung cancer is associated with downregulation of miR-17-5p expression which might cause upregulation of BECN1 expression.