Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer

Area of Science:

• Biochemistry
• Oncology
• Molecular Biology

Background:

• Glucose-6-phosphate dehydrogenase (G6PD) is crucial for NADPH production, maintaining reduced glutathione (GSH) to combat oxidative stress.
• Reactive oxygen species (ROS) play a dual role in cancer, influencing development and treatment response.
• Colorectal cancer (CRC) exhibits complex redox regulation impacting therapeutic outcomes.

Purpose of the Study:

• To investigate the role of G6PD in colorectal cancer (CRC) progression and chemoresistance.
• To evaluate G6PD as a prognostic biomarker for CRC patients.
• To explore G6PD as a therapeutic target for enhancing CRC chemotherapy.

Main Methods:

• Analysis of G6PD expression in CRC cell lines and patient tissues.
• Correlation of G6PD expression with clinical prognosis and oxaliplatin treatment outcomes.
• In vitro studies involving G6PD inhibition to assess effects on NADPH, GSH, ROS, and apoptosis.
• In vivo validation using xenograft and patient-derived xenograft (PDX) models with G6PD gene silencing.

Main Results:

• G6PD is significantly overexpressed in CRC cells and patient specimens.
• High G6PD expression correlates with poor prognosis and reduced efficacy of oxaliplatin chemotherapy in CRC.
• G6PD suppression leads to decreased NADPH and GSH, increased ROS, and enhanced oxaliplatin-induced apoptosis in CRC cells.
• Silencing G6PD potentiates oxaliplatin's anti-tumor effects in both cell-based xenografts and PDX models.

Conclusions:

• Disrupting G6PD-mediated NADPH homeostasis enhances oxaliplatin-induced apoptosis in CRC via redox modulation.
• G6PD serves as a potential prognostic biomarker for CRC.
• Targeting G6PD represents a promising therapeutic strategy for improving CRC treatment outcomes.