Journal
MOLECULAR BIOLOGY OF THE CELL
Volume 19, Issue 5, Pages 2220-2230Publisher
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E07-11-1170
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- National Science Council, Taiwan [NSC96-2120M-006-004]
- Center of Excellence for Clinical Trial and Research [DOH-TD-B-111-004]
- Department of Health, Executive Yuan, Taiwan
- Center for Gene Regulation and Signal Transduction Research, National Cheng Kung University, Taiwan
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We have demonstrated that soft substrate induced apoptosis in polarized cells, but not in transformed cells by disturbance of Ca2+ homeostasis. This study aims to further investigate the regulatory mechanisms underlying the disruption of Ca2+-signaling integrity in soft substrate-induced epithelial apoptosis. Soft substrate up-regulated the store-operated Ca2+ (SOC) entry across the plasma membrane of normal cervical epithelial cells, which resulted in increased cytosolic Ca2+ levels. Concomitantly, soft substrate induced the aggregation and translocation of stromal interacting molecule 1 ( STIM1) toward the cell periphery to colocalize with Orai1, an essential pore subunit of SOC channel, detected by fluorescence resonance energy transfer approach and confocal image analyses. The disturbed Ca2+ homeostasis resulted in the activation of mu-calpain, which cleaved mu-spectrin, induced actin disorganization, and caused apoptosis. In contrast, soft substrate did not disturb Ca2+ homeostasis or induce apoptosis in cervical cancer cells. Chelating extracellular Ca2+ by EGTA and down-regulated SOC entry by small interfering RNA targeting STIM1 or inhibitors targeting Ca2+-binding site of calpain significantly inhibited soft substrate-induced activation of mu-calpain and epithelial cell apoptosis. Thus, soft substrate up-regulates the interaction of STIM1 with SOC channels, which results in the activation of mu-calpain and subsequently induces normal epithelial cell apoptosis.
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