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Triptonide suppresses the FOXK1/AKT2 axis to reverse malignant phenotype and improve cisplatin efficacy in esophageal
Xiaoxu Li1, Liying Chen2, Zhaoyang Yan3
1Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China. xiaoxulihb@163.com.
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.
Insights
The FOXK1/AKT2 signaling pathway drives cisplatin resistance in esophageal squamous cell carcinoma (ESCC). Triptonide inhibits this axis, enhancing chemotherapy effectiveness in ESCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cisplatin resistance is a major challenge in esophageal squamous cell carcinoma (ESCC) chemotherapy.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- Investigate the role of the FOXK1/AKT2 axis in cisplatin resistance in ESCC.
- Evaluate triptonide's potential to overcome cisplatin resistance.
Main Methods:
- Assessed cisplatin sensitivity in ESCC cells with manipulated FOXK1 expression.
- Established cisplatin-resistant ESCC cell lines (TE1-R).
- Utilized luciferase reporter assays, cell viability, apoptosis, and gene expression analyses.
Main Results:
- FOXK1 overexpression decreased cisplatin sensitivity; FOXK1 knockdown restored it.
- FOXK1 directly activated AKT2 transcription, promoting proliferation and inhibiting apoptosis.
- Triptonide downregulated FOXK1/AKT2, reduced proliferation, induced apoptosis, and sensitized cells to cisplatin.
Conclusions:
- The FOXK1/AKT2 axis is a key driver of cisplatin resistance in ESCC.
- Triptonide effectively reverses cisplatin resistance by targeting the FOXK1/AKT2 pathway.
- This suggests triptonide as a potential therapeutic strategy to improve cisplatin efficacy in ESCC.
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