IP(3) Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer

Calcium ions (Ca(2+)) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca(2+) is shuffled between the cytoplasm and the major Ca(2+) stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca(2+) signals is attributed to the inositol 1,4,5-trisphosphate (IP(3)) receptors (IP(3)Rs), the main Ca(2+)-release channels in the ER. IP(3)Rs can transfer Ca(2+) to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP(3)-induced Ca(2+) release enhances autophagy flux by providing cytosolic Ca(2+) required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP(3)Rs are able to amplify Ca(2+) signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca(2+) release through IP(3)Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca(2+) ATPases Ca(2+) pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP(3)R and its cellular context in this disease. In cancer cells addicted to ER–mitochondrial Ca(2+) fueling, IP(3)R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP(3)Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca(2+) transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP(3)R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP(3)Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.