Role of oncogenic K-Ras in Ca²⁺ signalling Free

Ras is a small GTPase that controls a number of cell-fate-determining signalling pathways. Ras signalling is frequently deregulated in cancer, sometimes because of mutations in Ras itself, and this deregulation elicits most of the hallmarks of cancer cells. Consequently, inhibition of Ras is being considered in cancer therapies; however, as Ras functions in multiple pathways, transformed cells are often found to overcome drug targeting and develop resistance. Therefore, gaining a better understanding of the interplay between Ras and other signalling pathways is required. For instance, alterations in Ca²⁺ signalling have been reported in various cancers, but the underlying mechanisms and role of Ras in these alterations are not fully understood. On page 1607, Llewelyn Roderick and colleagues now compare Ca²⁺ signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the allele encoding mutated K-Ras (G13D) has been deleted by homologous recombination; this allows the identification of biological processes that are specifically controlled by K-RasG13D. Using this system, the authors demonstrate that depletion of K-RasG13D enhances inositol-triphosphate-dependent Ca²⁺ signalling, including increasing both Ca²⁺ release from the ER and Ca²⁺ levels in the ER, as well as augmenting ER–mitochondrial Ca²⁺ flux, which might sensitise cells to cell death stimuli. On the basis of these results, the authors suggest that K-RasG13D-mediated suppression of Ca²⁺ signalling from the ER and the reduced uptake of Ca²⁺ into mitochondria contributes to the pro-survival effects of mutated K-Ras that are associated with the oncogenic phenotype. These new insights might help to develop better therapeutic strategies to target oncogenic K-Ras.