Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) regulate autophagy in normal cells and are associated with metastasis in cancer cells. In breast cancer, however, the regulation and role of IP₃Rs is not clear. To study this, we used MCF-7 breast cancer cell line and mouse model of breast cancer. Inhibiting IP₃R sub types resulted in compromised bioenergetics both in terms of glucose and mitochondrial metabolism. The siRNA mediated silencing of IP₃R or its blocking by its inhibitors Xestospongin C and 2-Amino-ethoxy diphenyl borate increased cell death and LC3II expression in MCF-7 cells as well as attenuated cellular bioenergetics. The level of Autophagy related gene, Atg5 was found to be up regulated after pharmacological as well as siRNA blocking of IP₃R. The specificity of its role in autophagy was confirmed through specific shRNA knockdown of the Atg5 along with IP₃R inhibitor. Inhibiting as well as silencing of IP₃R receptor also resulted in increase in ROS production which was abolished after pretreatment with N-acetyl cysteine. Its role in autophagy was confirmed through decrease in the levels of LC3 II after pretreatment with IP₃R inhibitor and N acetyl cysteine.Moreover, inhibiting as well as silencing IP₃R-induced cell death in MCF-7 cells was attenuated by autophagic inhibitors (Bafilomycin A1 or 3-Methyladeneine). In mice, blocking of IP₃Rs by 2-Amino-ethoxy diphenyl borate arrested tumor growth. Overall our findings indicate that IP₃R blocking resulted in autophagic cell death in breast cancer cells and provides a role of IP₃Rs in determining the breast cancer cell fate. J. Cell. Biochem. 118: 2333–2346, 2017.