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.
Highlights
Ras proteins serve as molecular switches downstream of receptor tyrosine kinases and upstream of the Raf protein kinases (Cully and Downward, 2008; Downward, 2003a; Downward, 2003b; Schulze et al, 2004)
IP3-induced Ca2+ release is increased in cells deleted of K-RasG13D alterations in expression of a number of proteins involved in Ca2+ regulation in various tumour types and tumourderived cell lines have been described (Monteith et al, 2007), few studies have analysed how Ca2+ signalling is altered as a result of transformation
Consensus regarding how Ca2+ signalling participates in cellular transformation is lacking (Roderick and Cook, 2008). Contributing to this great variability is the problem in identifying appropriate experimental controls for the cancer cells studied and the issues associated with use of experimental systems in which pleiotropic oncogenes are expressed at supra-physiological levels (Tuveson et al, 2004)
Summary
Ras proteins serve as molecular switches downstream of receptor tyrosine kinases and upstream of the Raf protein kinases (Cully and Downward, 2008; Downward, 2003a; Downward, 2003b; Schulze et al, 2004) This pathway is frequently de-regulated in cancer due to mutation in receptor tyrosine kinases (RTKs) (e.g. EGFR), Ras itself (,20% of all human cancers) and BRaf (Downward, 2003b). Received 9 September 2013; Accepted 22 January 2014 regulators of multiple pathways involved in the regulation of cell cycle, metabolism and cell death – hallmarks of the transformed phenotype (Hanahan and Weinberg, 2000; Hanahan and Weinberg, 2011) This central role of Ras and the downstream pathways it engages have been targeted by the pharmaceutical industry in the development of cancer therapeutics. Drugs targeting the B-Raf–Mek–Erk pathway have been approved in the clinic (Belden and Flaherty, 2012; Little et al, 2013)
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