Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway

Qin He, Dong Lee, Rong Rong, Myounghee Yu, Xiuquan Luo, Michael Klein, Wafik S. El-Deiry, Ying Huang, Arif Hussain, M. Saeed Sheikh

Research output: Contribution to journalArticle

Abstract

Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, has been shown to induce apoptosis. The molecular mechanisms of Ca2+ perturbation-induced apoptosis are not fully understood. In this study, we demonstrate for the first time that TG-mediated perturbations in Ca2+ homeostasis are coupled with activation of the death receptor 5 (DR5)-dependent apoptotic pathway in human cancer cells. TG selectively upregulated DR5 but had no effect on the expression of the other TRAIL receptor, DR4. TG also upregulated the expression of the DR5 ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand), albeit in a cell-type specific manner. TG-induced apoptosis has been shown to be associated with activation of the mitochondrial pathway. We found that TG upregulation of DR5 and TRAIL was coupled with caspase 8 activation and Bid cleavage, suggesting that the TG-regulated DR5 pathway could be linked to the mitochondrial pathway. TG enhanced not only DR5 mRNA stability but also increased induction of the DR5 genomic promoter-reporter gene. The TG-induced increase in DR5 expression appeared to occur as a consequence of TG-induced endoplasmic reticulum (ER) Ca2+ pool depletion. Thus, we report our novel findings that ER Ca2+ pool depletion-induced apoptotic signals are mediated, at least in part, via a DR5-dependent apoptotic pathway and there appears to be a cross-talk between the death receptor and mitochondrial pathways.

Original languageEnglish (US)
Pages (from-to)2623-2633
Number of pages11
JournalOncogene
Volume21
Issue number17
DOIs
StatePublished - Apr 18 2002
Externally publishedYes

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Thapsigargin
Endoplasmic Reticulum
Apoptosis
Calcium
Homeostasis
Ligands
Death Domain Receptors
Caspase 8
RNA Stability
Reporter Genes
Up-Regulation
Tumor Necrosis Factor-alpha

Keywords

  • Apoptosis
  • Caspases
  • Death receptors
  • ER-stress
  • Thapsigargin
  • TRAIL

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway. / He, Qin; Lee, Dong; Rong, Rong; Yu, Myounghee; Luo, Xiuquan; Klein, Michael; El-Deiry, Wafik S.; Huang, Ying; Hussain, Arif; Sheikh, M. Saeed.

In: Oncogene, Vol. 21, No. 17, 18.04.2002, p. 2623-2633.

Research output: Contribution to journalArticle

He, Q, Lee, D, Rong, R, Yu, M, Luo, X, Klein, M, El-Deiry, WS, Huang, Y, Hussain, A & Sheikh, MS 2002, 'Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway', Oncogene, vol. 21, no. 17, pp. 2623-2633. https://doi.org/10.1038/sj.onc.1205345
He, Qin ; Lee, Dong ; Rong, Rong ; Yu, Myounghee ; Luo, Xiuquan ; Klein, Michael ; El-Deiry, Wafik S. ; Huang, Ying ; Hussain, Arif ; Sheikh, M. Saeed. / Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway. In: Oncogene. 2002 ; Vol. 21, No. 17. pp. 2623-2633.
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AB - Thapsigargin (TG), by inducing perturbations in cellular Ca2+ homeostasis, has been shown to induce apoptosis. The molecular mechanisms of Ca2+ perturbation-induced apoptosis are not fully understood. In this study, we demonstrate for the first time that TG-mediated perturbations in Ca2+ homeostasis are coupled with activation of the death receptor 5 (DR5)-dependent apoptotic pathway in human cancer cells. TG selectively upregulated DR5 but had no effect on the expression of the other TRAIL receptor, DR4. TG also upregulated the expression of the DR5 ligand TRAIL (tumor necrosis factor-related apoptosis inducing ligand), albeit in a cell-type specific manner. TG-induced apoptosis has been shown to be associated with activation of the mitochondrial pathway. We found that TG upregulation of DR5 and TRAIL was coupled with caspase 8 activation and Bid cleavage, suggesting that the TG-regulated DR5 pathway could be linked to the mitochondrial pathway. TG enhanced not only DR5 mRNA stability but also increased induction of the DR5 genomic promoter-reporter gene. The TG-induced increase in DR5 expression appeared to occur as a consequence of TG-induced endoplasmic reticulum (ER) Ca2+ pool depletion. Thus, we report our novel findings that ER Ca2+ pool depletion-induced apoptotic signals are mediated, at least in part, via a DR5-dependent apoptotic pathway and there appears to be a cross-talk between the death receptor and mitochondrial pathways.

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