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Inositol-triphosphate 3-kinase B confers cisplatin resistance by regulating NOX4-dependent redox balance.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2019 May 13; Vol. 129 (6), pp. 2431-2445. Date of Electronic Publication: 2019 May 13 (Print Publication: 2019). - Publication Year :
- 2019
-
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.
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 129
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 31081803
- Full Text :
- https://doi.org/10.1172/JCI124550