title: Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics.
abstract: 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. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Aru
authors.initials: A
authors.lastname: Singh
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Megha
authors.initials: M
authors.lastname: Chagtoo
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Swasti
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226017, India.
authors.forename: Nelson
authors.initials: N
authors.lastname: George
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.affiliation: Department of Endocrinology, Central Drug Research Institute, Lucknow, Uttar Pradesh 226031, India.
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Biochemistry, MS University Vadodara, Vadodara, Gujarat, India.
authors.forename: Sripada
authors.initials: S
authors.lastname: Lakshmi
authors.affiliation: Department of Molecular Medicine and Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
authors.forename: Madan M
authors.initials: MM
authors.lastname: Godbole
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D061986:MCF-7 Cells; D018942:Macrolides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D053496:Inositol 1,4,5-Trisphosphate Receptors; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C025946:3-methyladenine; C040929:bafilomycin A1; D000225:Adenine; D000111:Acetylcysteine
keywords: AUTOPHAGY; BIOENERGETICS; BREAST CANCER; CALCIUM CHANNELS; INSOSITOL 1,4,5 TRISPHOSPHATE RECEPTOR