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

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 Ca2+ signalling pathways control some overlapping functions with Ras, and altered Ca2+ signalling pathways are emerging as important players in oncogenic transformation, how Ca2+ signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca2+ 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 Ca2+ release from the endoplasmic reticulum (ER) intracellular Ca2+ stores is enhanced by loss of K-Ras(G13D) through an increase in the Ca2+ content of the ER store and a modification of the abundance of inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) subtypes. Consistently, uptake of Ca2+ into mitochondria and sensitivity to apoptosis was enhanced as a result of K-Ras(G13D) loss. These results suggest that suppression of Ca2+ signalling is a common response to naturally occurring levels of K-Ras(G13D), and that this contributes to a survival advantage during oncogenic transformation.