Capsazepine, a TRPV1 antagonist, sensitizes colorectal cancer cells to apoptosis by TRAIL through ROS-JNK-CHOP-mediated upregulation of death receptors

Bokyung Sung, Sahdeo Prasad, Jayaraj Ravindran, Vivek R. Yadav, Bharat B. Aggarwal

Research output: Contribution to journalArticlepeer-review

76 Scopus citations

Abstract

A major problem in clinical trials of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as cancer therapy is the development of resistance to TRAIL. Therefore, agents that can overcome TRAIL resistance have great therapeutic potential. In this study, we evaluated capsazepine, a TRPV1 antagonist, for its ability to sensitize human colon cancer cells to TRAIL-induced apoptosis. Capsazepine potentiated the effect of TRAIL, as shown by its effect on intracellular esterase activity; activation of caspase-8,-9, and -3; and colony-formation assay. Capsazepine induced death receptors (DRs) DR5 and DR4, but not decoy receptors, at the transcriptional level and in a non-cell-type-specific manner. DR induction was dependent on CCAAT/enhancer-binding protein homologous protein (CHOP), as shown by (a) the induction of CHOP by capsazepine and (b) the abolition of DR- and potentiation of TRAIL-induced apoptosis by CHOP gene silencing. CHOP induction was also reactive oxygen species (ROS)-dependent, as shown by capsazepine's ability to induce ROS and by the quenching of ROS by N-acetylcysteine or glutathione, which prevented induction of CHOP and DR5 and consequent sensitization to TRAIL. Capsazepine's effects appeared to be mediated via JNK, as shown by capsazepine's ability to induce JNK and by the suppression of both CHOP and DR5 activation by inhibition of JNK. Furthermore, ROS sequestration abrogated the activation of JNK. Finally, capsazepine downregulated the expression of various antiapoptotic proteins (e.g., cFLIP and survivin) and increased the expression of proapoptotic proteins (e.g., Bax and p53). Together, our results indicate that capsazepine potentiates the apoptotic effects of TRAIL through downregulation of cell survival proteins and upregulation of death receptors via the ROS-JNK-CHOP-mediated pathway.

Original languageEnglish (US)
Pages (from-to)1977-1987
Number of pages11
JournalFree Radical Biology and Medicine
Volume53
Issue number10
DOIs
StatePublished - Nov 15 2012

Keywords

  • Apoptosis
  • Death receptor
  • Free radicals
  • TRAIL
  • TRPV1 antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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