QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: E07-11-1170v1 19/5/2220    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Chiu, W.-T. Articles by Shen, M.-R. PubMed PubMed Citation Articles by Chiu, W.-T. Articles by Shen, M.-R.

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.