1. Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance.
- Author
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Pan C, Jin L, Wang X, Li Y, Chun J, Boese AC, Li D, Kang HB, Zhang G, Zhou L, Chen GZ, Saba NF, Shin DM, Magliocca KR, Owonikoko TK, Mao H, Lonial S, and Kang S
- Subjects
- A549 Cells, Animals, Female, Humans, Mice, Mice, Nude, NADPH Oxidase 4 genetics, Neoplasm Proteins genetics, Neoplasms drug therapy, Neoplasms genetics, Neoplasms pathology, Oxidation-Reduction drug effects, Phosphotransferases (Alcohol Group Acceptor) genetics, Xenograft Model Antitumor Assays, Cisplatin pharmacology, Drug Resistance, Neoplasm, NADPH Oxidase 4 metabolism, Neoplasm Proteins metabolism, Neoplasms enzymology, Phosphotransferases (Alcohol Group Acceptor) metabolism, Signal Transduction
- 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.
- Published
- 2019
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