HIF1α/VEGF Feedback Loop Contributes to 5-Fluorouracil Resistance

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• 5-Fluorouracil (5-Fu) is a cornerstone chemotherapy for colorectal cancer (CRC).
• Acquired drug resistance significantly limits 5-Fu efficacy in CRC treatment.
• Mechanisms underlying 5-Fu resistance in CRC remain incompletely understood.

Purpose of the Study:

• To investigate the role of hypoxia-inducible factor 1α (HIF1α) in 5-Fu resistance in colorectal cancer.
• To elucidate the molecular mechanisms linking HIF1α to drug resistance and malignant phenotype.
• To explore the potential of the HIF1α/VEGF pathway as a therapeutic target in CRC.

Main Methods:

• Screening for highly expressed proteins in 5-Fu resistant HCT115 cells.
• Investigating the effects of HIF1α suppression on epithelial-mesenchymal transition (EMT) and glucose transporter 1 (Glut1) expression.
• Analyzing the regulation of vascular endothelial growth factor (VEGF) by HIF1α.
• Examining the role of AKT/GSK3β signaling in HIF1α expression and the feedback loop with VEGF.
• Correlating HIF1α and VEGF expression with clinical data from CRC patients.

Main Results:

• HIF1α was highly expressed in 5-Fu resistant HCT115 cells exhibiting EMT.
• HIF1α suppression reversed EMT, reduced Glut1 expression, and attenuated drug resistance.
• VEGF was regulated by HIF1α and mediated the malignant phenotype in resistant cells.
• The AKT/GSK3β signaling pathway was activated in resistant cells, controlling HIF1α expression.
• VEGF was found to feedback-regulate HIF1α via the AKT/GSK3β pathway.
• High expression of HIF1α and VEGF correlated with poor survival and prognosis in CRC patients.

Conclusions:

• A HIF1α/VEGF feedback loop contributes significantly to 5-Fu resistance in colorectal cancer.
• This pathway, involving AKT/GSK3β signaling, represents a potential therapeutic strategy for overcoming 5-Fu resistance.
• Targeting HIF1α and VEGF may improve treatment outcomes for CRC patients.