AUTHOR=Kania Elzbieta , Roest Gemma , Vervliet Tim , Parys Jan B. , Bultynck Geert TITLE=IP3 Receptor-Mediated Calcium Signaling and Its Role in Autophagy in Cancer JOURNAL=Frontiers in Oncology VOLUME=7 YEAR=2017 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2017.00140 DOI=10.3389/fonc.2017.00140 ISSN=2234-943X ABSTRACT=

Calcium ions (Ca²⁺) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca²⁺ is shuffled between the cytoplasm and the major Ca²⁺ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca²⁺ signals is attributed to the inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs), the main Ca²⁺-release channels in the ER. IP₃Rs can transfer Ca²⁺ to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP₃-induced Ca²⁺ release enhances autophagy flux by providing cytosolic Ca²⁺ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mechanistic target of rapamycin inhibition, or drug treatment. Similarly, IP₃Rs are able to amplify Ca²⁺ signals from the lysosomes and, therefore, impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca²⁺ release through IP₃Rs may also be achieved by controlling the sarco/endoplasmic reticulum Ca²⁺ ATPases Ca²⁺ 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 IP₃R and its cellular context in this disease. In cancer cells addicted to ER–mitochondrial Ca²⁺ fueling, IP₃R inhibition leads to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP₃Rs 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 Ca²⁺ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP₃R-mediated upregulation of autophagy can protect some cancer cells against natural killer cells-induced killing. The involvement of IP₃Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.