Mitochondrial control of store-operated Ca channels in cancer: Pharmacological implications.

Intracellular Ca is a pleiotropic second messenger involved in control of different cell and physiological functions including long-term processes such as cell proliferation, migration and survival. Agonist-induced Ca entry in most cells, especially in non-excitable cells including epithelial cells, is mediated by store-operated Ca entry (SOCE), a Ca entry pathway activated by agonist-induced release of Ca from intracellular stores in the endoplasmic reticulum (ER). This pathway is modulated also by mitochondria which, acting as Ca sinks, take up Ca, thus limiting Ca-dependent inactivation of Ca-release activated Ca channels (CRAC). Compelling evidence shows that SOCE is upregulated in a large variety of cancer cells and this change contribute to cancer hallmarks. Mechanisms for enhanced SOCE include changes in expression of members of the Orai, Stromal interaction molecule (STIM) and canonical transient receptor potential channel (TRPc) gene families. Tumor cell mitochondria may contribute to SOCE upregulation in cancer as well. Molecular players involved in enhancing mitochondrial Ca uptake are upregulated in tumor cells whereas negative modulators are repressed. Furthermore, mitochondrial potential, the driving force for mitochondrial Ca uptake, is enhanced in tumor cells due to the Warburg effect. Finally, SOCE in tumor cells may be sustained further by the gain of function of non-selective TRPC channels permeable to Na that favour Ca exit from mitochondria in exchange for Na, thus limiting Ca-dependent inactivation of Orai1 channels. Therefore, tumor cell mitochondria may efficiently contribute to enhance and sustain SOCE in cancer. Interestingly, this effect could be counterbalanced by selected non-steroidal anti-inflammatory drugs (NSAIDs) reported to prevent colorectal cancer and other forms of cancer.