Ursolic acid induces ER stress response to activate ASK1-JNK signaling and induce apoptosis in human bladder cancer T24 cells

Cell Signal. 2013 Jan;25(1):206-13. doi: 10.1016/j.cellsig.2012.09.012. Epub 2012 Sep 18.

Abstract

Here we studied the cellular mechanisms of ursolic acid's anti-bladder cancer ability by focusing on endoplasmic reticulum stress (ER stress) signaling. We show that ursolic acid induces a significant ER stress response in cultured human bladder cancer T24 cells. ER stress inhibitor salubrinal, or PERK silencing, diminishes ursolic acid-induced anti-T24 cell effects. Salubrinal inhibits ursolic acid-induced CHOP expression, Bim ER accumulation and caspase-3 activation in T24 cells. Ursolic acid induces IRE1-TRAF2-ASK1 signaling complex formation to activate pro-apoptotic ASK1-JNK signaling. We suggest that ER stress contributes to ursolic acid's effects against bladder cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cinnamates / pharmacology
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoribonucleases / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Membrane Proteins / metabolism
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction / drug effects
  • TNF Receptor-Associated Factor 2 / metabolism
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacology
  • Transcription Factor CHOP / metabolism
  • Triterpenes / pharmacology*
  • Urinary Bladder Neoplasms
  • Ursolic Acid
  • eIF-2 Kinase / antagonists & inhibitors
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Antineoplastic Agents, Phytogenic
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • Bcl-2-Like Protein 11
  • Cinnamates
  • DDIT3 protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • TNF Receptor-Associated Factor 2
  • Triterpenes
  • salubrinal
  • Transcription Factor CHOP
  • ERN2 protein, human
  • PERK kinase
  • Protein Serine-Threonine Kinases
  • eIF-2 Kinase
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • Endoribonucleases
  • Caspase 3
  • Thiourea