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Inhibition of Inositol 1, 4, 5‐Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics
Author(s) -
Singh Aru,
Chagtoo Megha,
Tiwari Swasti,
George Nelson,
Chakravarti Bandana,
Khan Sajid,
Lakshmi Sripada,
Godbole Madan M.
Publication year - 2017
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.25891
Subject(s) - autophagy , atg5 , cancer cell , programmed cell death , microbiology and biotechnology , gene silencing , receptor , inositol , biology , cancer research , chemistry , cancer , apoptosis , biochemistry , genetics , gene
ABSTRACT Inositol 1,4,5‐trisphosphate receptors (IP 3 Rs) regulate autophagy in normal cells and are associated with metastasis in cancer cells. In breast cancer, however, the regulation and role of IP 3 Rs is not clear. To study this, we used MCF‐7 breast cancer cell line and mouse model of breast cancer. Inhibiting IP 3 R sub types resulted in compromised bioenergetics both in terms of glucose and mitochondrial metabolism. The siRNA mediated silencing of IP 3 R 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 IP 3 R. The specificity of its role in autophagy was confirmed through specific shRNA knockdown of the Atg5 along with IP 3 R inhibitor. Inhibiting as well as silencing of IP 3 R 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 IP 3 R inhibitor and N acetyl cysteine.Moreover, inhibiting as well as silencing IP 3 R‐induced cell death in MCF‐7 cells was attenuated by autophagic inhibitors (Bafilomycin A1 or 3‐Methyladeneine). In mice, blocking of IP 3 Rs by 2‐Amino‐ethoxy diphenyl borate arrested tumor growth. Overall our findings indicate that IP 3 R blocking resulted in autophagic cell death in breast cancer cells and provides a role of IP 3 Rs in determining the breast cancer cell fate. J. Cell. Biochem. 118: 2333–2346, 2017. © 2017 Wiley Periodicals, Inc.