title: A reciprocal shift in transient receptor potential channel 1 (TRPC1) and stromal interaction molecule 2 (STIM2) contributes to Ca2+ remodeling and cancer hallmarks in colorectal carcinoma cells.
abstract: We have investigated the molecular basis of intracellular Ca(2+) handling in human colon carcinoma cells (HT29) versus normal human mucosa cells (NCM460) and its contribution to cancer features. We found that Ca(2+) stores in colon carcinoma cells are partially depleted relative to normal cells. However, resting Ca(2+) levels, agonist-induced Ca(2+) increases, store-operated Ca(2+) entry (SOCE), and store-operated currents (ISOC) are largely enhanced in tumor cells. Enhanced SOCE and depleted Ca(2+) stores correlate with increased cell proliferation, invasion, and survival characteristic of tumor cells. Normal mucosa cells displayed small, inward Ca(2+) release-activated Ca(2+) currents (ICRAC) mediated by ORAI1. In contrast, colon carcinoma cells showed mixed currents composed of enhanced ICRAC plus a nonselective ISOC mediated by TRPC1. Tumor cells display increased expression of TRPC1, ORAI1, ORAI2, ORAI3, and STIM1. In contrast, STIM2 protein was nearly depleted in tumor cells. Silencing data suggest that enhanced ORAI1 and TRPC1 contribute to enhanced SOCE and differential store-operated currents in tumor cells, whereas ORAI2 and -3 are seemingly less important. In addition, STIM2 knockdown decreases SOCE and Ca(2+) store content in normal cells while promoting apoptosis resistance. These data suggest that loss of STIM2 may underlie Ca(2+) store depletion and apoptosis resistance in tumor cells. We conclude that a reciprocal shift in TRPC1 and STIM2 contributes to Ca(2+) remodeling and tumor features in colon cancer.
authors.affiliation: From the Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Sobradillo
authors.affiliation: From the Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Hernández-Morales
authors.affiliation: From the Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), 47003 Valladolid, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ubierna
authors.affiliation: INCELL Corp., San Antonio, Texas 78249, and.
authors.forename: Mary P
authors.initials: MP
authors.lastname: Moyer
authors.affiliation: the Department of Biochemistry and Molecular Biology and Physiology, University of Valladolid, 47003 Valladolid, Spain.
authors.forename: Lucía
authors.initials: L
authors.lastname: Núñez
authors.affiliation: From the Institute of Molecular Biology and Genetics (IBGM), Spanish National Research Council (CSIC), 47003 Valladolid, Spain, carlosv@ibgm.uva.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Villalobos
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D063646:Carcinogenesis; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism*; D055724:Electrophysiological Phenomena; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000737:chemistry; D007413:Intestinal Mucosa / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium
keywords: Calcium; Calcium Imaging; Calcium Release-activated Calcium Channel Protein 1 (ORAI1); Cell Proliferation; Colon Cancer; Stromal Interaction Molecule 1 (STIM1)