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.
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Acknowledgements
Part of this work was initiated at the NCI/NIH and MS Sheikh thanks Ms Kia Brooks for help with the Northern blot analyses. This work was supported in part by United States Army Prostate Cancer Research Program grant DAMD 170010722 and NIH grant CA89043 to MS Sheikh and a Merit Review Award from the Medical Research Services of the Department of Veterans Affairs to A Hussain and National Institutes of Health Grant PO1HL27867.
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He, Q., Lee, D., Rong, R. et al. Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway. Oncogene 21, 2623–2633 (2002). https://doi.org/10.1038/sj.onc.1205345
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DOI: https://doi.org/10.1038/sj.onc.1205345
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