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

Aru Singh, Megha Chagtoo, Swasti Tiwari, Nelson George, Bandana Chakravarti, Sajid Khan, Sripada Lakshmi, Madan M. Godbole

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2333-2346
Number of pages14
JournalJournal of Cellular Biochemistry
Volume118
Issue number8
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

Keywords

  • AUTOPHAGY
  • BIOENERGETICS
  • BREAST CANCER
  • CALCIUM CHANNELS
  • INSOSITOL 1,4,5 TRISPHOSPHATE RECEPTOR

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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