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