Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance

• Type of Material: Article
• Authors: Chaoyun Pan, Emory University; Lingtao Jin, Emory University; Xu Wang, Emory University; Yuancheng Li, Emory University; Jaemoo Chun, Emory University; Austin C. Boese, Emory University; Dan Li, Emory University; Hee-Bum Kang, Emory University; Guojing Zhang, Emory University; Lu Zhou, University of Chicago; Georgia Chen, Emory University; Nabil F Saba, Emory University; Dong M Shin, Emory University; Kelly R. Magliocca, Emory University; Taofeek K Owonikoko, Emory University; Hui Mao, Emory University; Sagar Lonial, Emory University; Sumin Kang, Emory University
• Language: English
• Date: 2019-06-03
• Publisher: American Society for Clinical Investigation
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2019, American Society for Clinical Investigation.
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI124550
• Title of Journal or Parent Work: Journal of Clinical Investigation
• ISSN: 0021-9738
• Volume: 129
• Issue: 6
• Start Page: 2431
• End Page: 2445
• Grant/Funding Information: This work was supported in part by NIH grants R01 CA175316 (to SK) and R01 CA207768 (to SK); Department of Defense grant W81XWH-17-1-0186 (to SK); Developmental Funds from the Winship Cancer Institute of Emory University (to SK); Winship Cancer Institute IRG-17-181-04 from the American Cancer Society (to LJ); and the Emory University Integrated Cellular Imaging Microscopy Core of the Winship Cancer Institute Comprehensive Cancer Center, grant 2P30CA138292.; SK is a Georgia Cancer Coalition Scholar, a Robbins Scholar, and an American Cancer Society Basic Research Scholar.
• Keywords: Research & Experimental Medicine; EXPRESSION; Life Sciences & Biomedicine; ROS; PROLIFERATION; SELECTION; Medicine, Research & Experimental; OXIDASES; OVARIAN-CANCER CELLS; METABOLISM; HOMEOSTASIS; ROLES; Science & Technology; INHIBITOR
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Health Sciences, Radiology

Abstract

How altered metabolism contributes to chemotherapy resistance in cancer cells remains unclear. Through a metabolism-related kinome RNAi screen, we identified inositol-trisphosphate 3-kinase B (ITPKB) as a critical enzyme that contributes to cisplatin-resistant tumor growth. We demonstrated that inositol 1,3,4,5-tetrakisphosphate (IP4), the product of ITPKB, plays a critical role in redox homeostasis upon cisplatin exposure by reducing cisplatin-induced ROS through inhibition of a ROS-generating enzyme, NADPH oxidase 4 (NOX4), which promotes cisplatin-resistant tumor growth. Mechanistically, we identified that IP4 competes with the NOX4 cofactor NADPH for binding and consequently inhibits NOX4. Targeting ITPKB with shRNA or its small-molecule inhibitor resulted in attenuation of NOX4 activity, imbalanced redox status, and sensitized cancer cells to cisplatin treatment in patient-derived xenografts. Our findings provide insight into the crosstalk between kinase-mediated metabolic regulation and platinum-based chemotherapy resistance in human cancers. Our study also suggests a distinctive signaling function of IP4 that regulates NOX4. Furthermore, pharmaceutical inhibition of ITPKB displayed synergistic attenuation of tumor growth with cisplatin, suggesting ITPKB as a promising synthetic lethal target for cancer therapeutic intervention to overcome cisplatin resistance.