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Vol. 19, Issue 5, 2220-2230, May 2008

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Soft Substrate Up-regulates the Interaction of STIM1 with Store-operated Ca²⁺ Channels That Lead to Normal Epithelial Cell Apoptosis

Wen-Tai Chiu^*, Ming-Jer Tang^,, Hsiao-Chun Jao, and Meng-Ru Shen^,,||

*Institute of Basic Medical Sciences, Department of Physiology, Center for Gene Regulation and Signal Transduction Research, and Departments of Pharmacology and ^||Obstetrics and Gynecology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan

Submitted November 21, 2007; Revised February 12, 2008; Accepted February 29, 2008
Monitoring Editor: Yu-Li Wang

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 µ-calpain, which cleaved -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 µ-calpain and epithelial cell apoptosis. Thus, soft substrate up-regulates the interaction of STIM1 with SOC channels, which results in the activation of µ-calpain and subsequently induces normal epithelial cell apoptosis.

Address correspondence to: Meng-Ru Shen (mrshen{at}mail.ncku.edu.tw)

Abbreviations used: [Ca²⁺]_i, intracellular Ca²⁺; [Ca²⁺]_o, extracellular Ca²⁺; ER, endoplasmic reticulum; SOC channel, store-operated Ca²⁺ channel; STIM1, stromal interacting molecule 1.

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