title: Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.
abstract: Store-operated Ca(2+) entry (SOCE) is the principal Ca(2+) entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca(2+) sensor that triggers SOCE activation. However, the role of STIM1 in regulating cancer progression remains controversial and its clinical relevance is unclear. Here we show that STIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis. STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumor tissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival. EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interaction between STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca(2+) influx. STIM1 involves the activation of Ca(2+)-regulated protease calpain, as well as Ca(2+)-regulated cytoplasmic kinase Pyk2, which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 also regulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockade of SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role of STIM1-mediated Ca(2+) influx in aggravating tumor development in vivo. These results make STIM1-dependent signaling an attractive target for therapeutic intervention.
authors.affiliation: Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Yih-Fung
authors.initials: YF
authors.lastname: Chen
authors.forename: Wen-Tai
authors.initials: WT
authors.lastname: Chiu
authors.forename: Ying-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Pey-Yun
authors.initials: PY
authors.lastname: Lin
authors.forename: Huey-Jy
authors.initials: HJ
authors.lastname: Huang
authors.forename: Cheng-Yang
authors.initials: CY
authors.lastname: Chou
authors.forename: Hsien-Chang
authors.initials: HC
authors.lastname: Chang
authors.forename: Ming-Jer
authors.initials: MJ
authors.lastname: Tang
authors.forename: Meng-Ru
authors.initials: MR
authors.lastname: Shen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D000071740:ORAI1 Protein; D015398:Signal Transduction / Q000187:drug effects; D000071737:Stromal Interaction Molecule 1; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000098:blood supply* / Q000473:pathology*
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D004815:Epidermal Growth Factor; D002118:Calcium