Salinomycin induces cell death with autophagy through activation of endoplasmic reticulum stress in human cancer cells

Autophagy. 2013 Jul;9(7):1057-68. doi: 10.4161/auto.24632. Epub 2013 Apr 18.

Abstract

Salinomycin is perhaps the first promising compound that was discovered through high throughput screening in cancer stem cells. This novel agent can selectively eliminate breast and other cancer stem cells, though the mechanism of action remains unclear. In this study, we found that salinomycin induced autophagy in human non-small cell lung cancer (NSCLC) cells. Furthermore, we demonstrated that salinomycin stimulated endoplasmic reticulum stress and mediated autophagy via the ATF4-DDIT3/CHOP-TRIB3-AKT1-MTOR axis. Moreover, we found that the autophagy induced by salinomycin played a prosurvival role in human NSCLC cells and attenuated the apoptotic cascade. We also showed that salinomycin triggered more apoptosis and less autophagy in A549 cells in which CDH1 expression was inhibited, suggesting that the inhibition of autophagy might represent a promising strategy to target cancer stem cells. In conclusion, these findings provide evidence that combination treatment with salinomycin and pharmacological autophagy inhibitors will be an effective therapeutic strategy for eliminating cancer cells as well as cancer stem cells.

Keywords: MTOR; apoptosis; autophagy; endoplasmic reticulum stress; salinomycin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Antigens, CD
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Cadherins / metabolism
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cytoprotection / drug effects
  • Drug Screening Assays, Antitumor
  • Endoplasmic Reticulum Stress / drug effects*
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrans / pharmacology*
  • Repressor Proteins / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factor CHOP / metabolism
  • Up-Regulation / drug effects

Substances

  • ATF4 protein, human
  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Cell Cycle Proteins
  • DDIT3 protein, human
  • Pyrans
  • Repressor Proteins
  • TRIB3 protein, human
  • Activating Transcription Factor 4
  • Transcription Factor CHOP
  • salinomycin
  • MTOR protein, human
  • AKT1 protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases