Triptonide suppresses the FOXK1/AKT2 axis to reverse malignant phenotype and improve cisplatin efficacy in esophageal squamous cell carcinoma.

BACKGROUND

Cisplatin resistance significantly limits the effectiveness of chemotherapy in esophageal squamous cell carcinoma (ESCC). Understanding the molecular mechanisms driving resistance is essential for improving treatment outcomes.

OBJECTIVE

This study aimed to investigate the role of the FOXK1/AKT2 axis in cisplatin resistance in ESCC cells and to evaluate the potential of triptonide in reversing this resistance.

METHODS

Cisplatin sensitivity was assessed in ESCC cell lines with altered FOXK1 expression. A cisplatin-resistant TE1 cell line (TE1-R) was established by prolonged low-dose cisplatin exposure. Luciferase reporter assays were conducted to determine whether FOXK1 activates AKT2 transcription. Cell viability, colony formation, apoptosis assays, and expression analysis of apoptosis-related genes were performed to examine the effects of FOXK1, AKT2, and triptonide.

RESULTS

FOXK1 overexpression reduced cisplatin sensitivity in ESCC cells, while FOXK1 knockdown restored sensitivity in TE1-R cells. FOXK1 directly enhanced AKT2 transcription by binding to its promoter region. The FOXK1/AKT2 axis promoted cell proliferation and suppressed cisplatin-induced apoptosis. Triptonide treatment downregulated FOXK1 and AKT2 expression, inhibited proliferation, induced apoptosis, and sensitized ESCC cells to cisplatin in a synergistic manner.

CONCLUSIONS

The FOXK1/AKT2 signaling axis contributes to cisplatin resistance in ESCC. Triptonide reverses resistance by inhibiting this axis, offering a promising strategy to enhance cisplatin efficacy in ESCC therapy.