1. Capsaicin-induced apoptosis is regulated by endoplasmic reticulum stress- and calpain-mediated mitochondrial cell death pathways
- Author
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Seon-Hee Oh, Mi-Ja Lee, Sung-Chul Lim, Keun-Hong Kee, and Chae-Hong Suh
- Subjects
Proteasome Endopeptidase Complex ,Programmed cell death ,Time Factors ,Cell Survival ,Leupeptins ,Apoptotic nuclear changes ,Apoptosis ,Cysteine Proteinase Inhibitors ,Protein Serine-Threonine Kinases ,Endoplasmic Reticulum ,Toxicology ,Cell Line ,chemistry.chemical_compound ,Stress, Physiological ,Endoribonucleases ,MG132 ,Humans ,Calcium Signaling ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Cell Proliferation ,Membrane Potential, Mitochondrial ,Dose-Response Relationship, Drug ,biology ,Calpain ,Tunicamycin ,Endoplasmic reticulum ,Apoptosis Inducing Factor ,Cytochromes c ,Membrane Proteins ,Epithelial Cells ,Mitochondria ,Cell biology ,Enzyme Activation ,Protein Transport ,chemistry ,Caspases ,biology.protein ,Unfolded protein response ,Apoptosis-inducing factor ,Capsaicin ,Tumor Suppressor Protein p53 ,Transcription Factor CHOP ,BH3 Interacting Domain Death Agonist Protein ,Signal Transduction - Abstract
Capsaicin, a pungent compound found in hot chili peppers, induces apoptotic cell death in various cell lines, however, the precise apoptosis signaling pathway is unknown. Here, we investigated capsaicin-induced apoptotic signaling in the human breast cell line MCF10A and found that it involves both endoplasmic reticulum (ER) stress and calpain activation. Capsaicin inhibited growth in a dose-dependent manner and induced apoptotic nuclear changes in MCF10A cells. Capsaicin also induced degradation of tumor suppressor p53; this effect was enhanced by the ER stressor tunicamycin. The proteasome inhibitor MG132 completely blocked capsaicin-induced p53 degradation and enhanced apoptotic cell death. Capsaicin treatment triggered ER stress by increasing levels of IRE1, GADD153/Chop, GRP78/Bip, and activated caspase-4. It led to an increase in cytosolic Ca(2+), calpain activation, loss of the mitochondrial transmembrane potential, release of mitochondrial cytochrome c, and caspase-9 and -7 activation. Furthermore, capsaicin-induced the mitochondrial apoptotic pathway through calpain-mediated Bid translocation to the mitochondria and nuclear translocation of apoptosis-inducing factor (AIF). Capsaicin-induced caspase-9, Bid cleavage, and AIF translocation were blocked by calpeptin, and BAPTA and calpeptin attenuated calpain activation and Bid cleavage. Thus, both ER stress- and mitochondria-mediated death pathways are involved in capsaicin-induced apoptosis.
- Published
- 2009