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.
Highlights
Reviewed by: Frank Kruyt, University Medical Center Groningen, Netherlands Hamid Morjani, University of Reims ChampagneArdenne, France
Cancer cells appear to be addicted to IP3R-mediated Ca2+ release to sustain their mitochondrial metabolism and related anabolic pathways
Cancer cells exposed to IP3R inhibition can undergo cell death, which in some cases could be due to excessive autophagy induction, while in other cases cell death could be the result of an uncontrolled cell proliferation and be due to mitotic catastrophe
Summary
Autophagy is a basic catabolic process, existing in all types of cells, where it functions mostly in controlling protein turnover and sustaining energetic balance [132]. Treatment of cells expressing oncogenic PML fusion protein with this drug resulted in PML-RARα degradation and rescued wild-type PML levels, which was present in the MAMs and able to promote ER–mitochondrial Ca2+ transfer [168] Another tumor suppressor actively involved in autophagy regulation is Beclin 1. Many tumors display low TMX1 levels, which results in increased SERCA activity, at the MAMs, leading to dampened ER–mitochondrial Ca2+ transfer (Figure 2C) This was proposed to contribute to the Warburg effect and increased glycolysis, as the activity of TCA cycle enzymes became suppressed, while the need for glucose metabolism remained high to sustain cell growth and proliferation [174, 175]. IP3R-Regulated Autophagy As a Protection against Natural Killer (NK)-Induced Cancer
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