title: Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodelling of the isoform composition of IP₃Rs and ER luminal Ca²⁺ levels in colorectal cancer cell lines.
abstract: The GTPase Ras is a molecular switch engaged downstream of G-protein-coupled receptors and receptor tyrosine kinases that controls multiple cell-fate-determining signalling pathways. Ras signalling is frequently deregulated in cancer, underlying associated changes in cell phenotype. Although Ca(2+) signalling pathways control some overlapping functions with Ras, and altered Ca(2+) signalling pathways are emerging as important players in oncogenic transformation, how Ca(2+) signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca(2+) signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the allele encoding oncogenic K-Ras (G13D) was deleted by homologous recombination. We show that agonist-induced Ca(2+) release from the endoplasmic reticulum (ER) intracellular Ca(2+) stores is enhanced by loss of K-Ras(G13D) through an increase in the Ca(2+) content of the ER store and a modification of the abundance of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) subtypes. Consistently, uptake of Ca(2+) into mitochondria and sensitivity to apoptosis was enhanced as a result of K-Ras(G13D) loss. These results suggest that suppression of Ca(2+) signalling is a common response to naturally occurring levels of K-Ras(G13D), and that this contributes to a survival advantage during oncogenic transformation.
authors: Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT UK.
authors: Cristina
authors: C
authors: Pierro
authors: Simon J
authors: SJ
authors: Cook
authors: Thomas C F
authors: TC
authors: Foets
authors: Martin D
authors: MD
authors: Bootman
authors: H Llewelyn
authors: HL
authors: Roderick
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D015544:Inositol 1,4,5-Trisphosphate; D018631:ras Proteins; D002118:Calcium
keywords: Ca2+, Mitochondria; Cancer; IP3; Inositol 1,4,5-trisphosphate; K-Ras