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

Area of Science:

• Oncology
• Cancer Metabolism
• Chemotherapy Resistance

Background:

• Altered cellular metabolism is implicated in chemotherapy resistance, but specific mechanisms remain elusive.
• Identifying key metabolic regulators is crucial for developing strategies to overcome treatment failure.

Purpose of the Study:

• To identify metabolic enzymes contributing to cisplatin resistance using a kinome-wide RNAi screen.
• To elucidate the role of inositol-trisphosphate 3-kinase B (ITPKB) in mediating resistance to platinum-based chemotherapy.

Main Methods:

• Conducted a metabolism-related kinome RNAi screen to identify genes involved in cisplatin resistance.
• Investigated the role of ITPKB and its product, inositol 1,3,4,5-tetrakisphosphate (IP4), in regulating cellular redox homeostasis.
• Assessed the interaction between IP4 and NADPH oxidase 4 (NOX4) and its impact on reactive oxygen species (ROS) production.
• Evaluated the efficacy of targeting ITPKB using shRNA and small-molecule inhibitors in patient-derived xenografts.

Main Results:

• ITPKB was identified as a critical enzyme promoting cisplatin-resistant tumor growth.
• IP4, produced by ITPKB, reduces cisplatin-induced ROS by inhibiting NOX4 activity.
• IP4 competes with NADPH for NOX4 binding, thereby inhibiting ROS generation.
• Targeting ITPKB attenuated NOX4 activity, rebalanced redox status, and sensitized cancer cells to cisplatin in vivo.

Conclusions:

• ITPKB plays a significant role in platinum-based chemotherapy resistance through metabolic regulation of redox homeostasis.
• IP4 exhibits a novel signaling function by regulating NOX4 activity.
• Pharmaceutical inhibition of ITPKB demonstrates synergistic effects with cisplatin, positioning ITPKB as a potential therapeutic target to overcome cisplatin resistance.