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Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance
Chaoyun Pan, … , Sagar Lonial, Sumin Kang
Chaoyun Pan, … , Sagar Lonial, Sumin Kang
Published June 3, 2019; First published May 13, 2019
Citation Information: J Clin Invest. 2019;129(6):2431-2445. https://doi.org/10.1172/JCI124550.
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Categories: Research Article Cell biology Metabolism

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

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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.

Authors

Chaoyun Pan, Lingtao Jin, Xu Wang, Yuancheng Li, Jaemoo Chun, Austin C. Boese, Dan Li, Hee-Bum Kang, Guojing Zhang, Lu Zhou, Georgia Z. Chen, Nabil F. Saba, Dong M. Shin, Kelly R. Magliocca, Taofeek K. Owonikoko, Hui Mao, Sagar Lonial, Sumin Kang

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Figure 7

The ITPKB product IP4 directly binds to NOX4 and suppresses its activity by competing with the cofactor NADPH for binding.

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The ITPKB product IP4 directly binds to NOX4 and suppresses its activity...
(A) Purification of the recombinant NOX4 dehydrogenase active domain (NOX4-DH). Top: Schematic representation of NOX4 domains. TM, transmembrane domain; FAD, flavin adenine dinucleotide binding domain; NADPH, NADPH binding domain. Bottom: Coomassie staining of purified recombinant NOX4-DH. (B) Thermal shift analyses of NOX4-DH incubated with increasing concentrations of IP4. Tm, melting temperature. (C) Thermal shift analyses of NOX4-DH incubated with 80 μM of the inositol metabolites PIP3, IP3, IP4, and IP5. Dissociation constant (KD) values for the interaction are shown. ND, not determined. (D) Interaction between IP4 and NOX4-DH was determined by Biacore surface plasmon resonance analysis and is shown as a KD value. (E and F) The activity of purified NOX4-DH was measured in the presence of increasing concentrations of IP4 (E) or 80 μM of different inositol metabolites (F). (G) Quantification of NADPH bound to NOX4 in the presence of increasing concentrations of IP4. FLAG-tagged NOX4-DH (30 μM) was incubated with NADPH (100 μM) and IP4 (0–100 μM). Amount of NADPH retained on immobilized NOX4-DH was determined by measurement of absorbance at A340 nm. Data are mean ± SD from 3 technical replicates of each sample for E–G. Data shown are representative of 2 (B–D) and 3 (E–G) independent biological experiments. Statistical analysis was performed by 1-way ANOVA (****P < 0.0001).
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