ER Ca 2+ release and store-operated Ca 2+ entry - partners in crime or independent actors in oncogenic transformation?

Ca is a pleiotropic messenger that controls life and death decisions from fertilisation until death. Cellular Ca handling mechanisms show plasticity and are remodelled throughout life to meet the changing needs of the cell. In turn, as the demands on a cell alter, for example through a change in its niche environment or its functional requirements, Ca handling systems may be targeted to sustain the remodelled cellular state. Nowhere is this more apparent than in cancer. Oncogenic transformation is a multi-stage process during which normal cells become progressively differentiated towards a cancerous state that is principally associated with enhanced proliferation and avoidance of death. Ca signalling is intimately involved in almost all aspects of the life of a transformed cell and alterations in Ca handling have been observed in cancer. Moreover, this remodelling of Ca signalling pathways is also required in some cases to sustain the transformed phenotype. As such, Ca handling is hijacked by oncogenic processes to deliver and maintain the transformed phenotype. Central to generation of intracellular Ca signals is the release of Ca from the endoplasmic reticulum intracellular (ER) Ca store via inositol 1,4,5-trisphosphate receptors (InsP Rs). Upon depletion of ER Ca , store-operated Ca entry (SOCE) across the plasma membrane occurs via STIM-gated Orai channels. SOCE serves to both replenish stores but also sustain Ca signalling events. Here, we will discuss the role and regulation of these two signalling pathways and their interplay in oncogenic transformation.