Mitochondrial control of store-operated Ca2+ channels in cancer: Pharmacological implications

Abstract

Intracellular Ca²⁺ 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 Ca²⁺ entry in most cells, especially in non-excitable cells including epithelial cells, is mediated by store-operated Ca²⁺ entry (SOCE), a Ca²⁺ entry pathway activated by agonist-induced release of Ca²⁺ from intracellular stores in the endoplasmic reticulum (ER). This pathway is modulated also by mitochondria which, acting as Ca²⁺ sinks, take up Ca²⁺, thus limiting Ca²⁺-dependent inactivation of Ca²⁺-release activated Ca²⁺ 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 Ca²⁺ uptake are upregulated in tumor cells whereas negative modulators are repressed. Furthermore, mitochondrial potential, the driving force for mitochondrial Ca²⁺ 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 Ca²⁺ exit from mitochondria in exchange for Na⁺, thus limiting Ca²⁺-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.

Keywords: Colorectal cancer; Mitochondria; Non-steroidal anti-inflammatory drugs; Store-operated Ca(2+)entry; Store-operated currents; Warburg effect.