miR-17-5p downregulation contributes to paclitaxel resistance of lung cancer cells through altering beclin1 expression

PLoS One. 2014 Apr 22;9(4):e95716. doi: 10.1371/journal.pone.0095716. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / chemistry
  • Apoptosis Regulatory Proteins / genetics*
  • Autophagy / drug effects
  • Autophagy / genetics
  • Base Sequence
  • Beclin-1
  • Binding Sites
  • Cell Line, Tumor
  • Cluster Analysis
  • Cytochromes c / metabolism
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lung Neoplasms / genetics*
  • Membrane Potential, Mitochondrial / drug effects
  • Membrane Potential, Mitochondrial / genetics
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Paclitaxel / pharmacology*
  • RNA, Messenger / genetics
  • Reactive Oxygen Species / metabolism

Substances

  • 3' Untranslated Regions
  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • MIRN17 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • RNA, Messenger
  • Reactive Oxygen Species
  • Cytochromes c
  • Paclitaxel

Grant support

The work was supported by a grant from the Department of Biotechnology, Govt. of India (No. BT/PR12889/AGR/36/624/2009) to GC. AC was supported by a fellowship from the same grant, and subsequently, a fellowship from DST- PURSE programme, University of Calcutta. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.