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 May 13, 2019
Citation Information: J Clin Invest. 2019;129(6):2431-2445. https://doi.org/10.1172/JCI124550.
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Research Article Cell biology Metabolism

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

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 1

ITPKB upregulation is associated with cisplatin resistance in diverse cancer cell lines and primary patient samples.

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ITPKB upregulation is associated with cisplatin resistance in diverse ca...
(A) RNAi screen result using 16 candidate kinases that phosphorylate metabolites selected among the top 100 leading candidates from a kinome shRNA library. Cancer cell lines (KB-3-1cisR, A549cisR, A2780cisR) were treated with pooled shRNA clones and sublethal doses of cisplatin (KB-3-1cisR, 5 μg/ml; A549cisR, 1 μg/ml; A2780cisR, 2.5 μg/ml) for 48 hours. Cell viability was assessed using CellTiter-Glo Luminescent cell viability assay. Minimum and maximum are at the ends of the whiskers. (B and C) The correlation between ITPKB protein level and cisplatin IC50 in a panel of cancer cell lines (B) and patient-derived xenograft (PDX) tumors (C). (D) Immunohistochemistry analyses of ITPKB in primary tumor specimens collected from head and neck squamous cell carcinoma (HNSCC) patients treated with platinum therapy. Tumors from HNSCC patient groups who showed response (blue) or no response (red) to platinum therapy within a 2-year duration are compared. Data are mean ± SD of 3 technical replicates for A and are representative of 3 (A) and 2 (B and C) independent biological experiments. Data are mean ± SD from indicated sample numbers (n = 13 and n = 29) for D. Statistical analyses were performed by 1-way ANOVA (A), 2-tailed Pearson’s correlation coefficient (B and C), and unpaired 2-tailed Student’s t test (D) (*P < 0.05; **P < 0.01; ***P < 0.005).