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p38 Mitogen-activated protein kinase modulates cisplatin resistance in Head and Neck Squamous Cell Carcinoma cells
Shomereeta Roy1, Souvick Roy1, Kumari Anuja1
1Molecular Stress and Stem Cell Biology Group, School of Biotechnology, KIIT, Bhubaneswar, Odisha 751024, India.
Objective:
This study aims to investigate the role of p38 Mitogen-activated protein kinase (MAPK) in imparting cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) cells.
Design:
Laboratory generated cisplatin resistant HNSCC cells were treated with p38 inhibitor and were subjected to increasing dosage of cisplatin. Western blot, immunohistochemistry and RT PCR analysis were performed to investigate expression level of p-p38 and Cancer stem cell (CSC) markers in cisplatin resistant HNSCC cells with or without p38 inhibitor. Chemoresistance, wound healing capacity and Spheroids formation capacity were assessed following p38 inhibition in cisplatin resistant HNSCC cell lines. In addition, alkaline comet assay and γ-H2AX immunostaining were performed to evaluate the DNA damage response and repair abilities in cisplatin resistant HNSCC cells after p38 inhibition.
Results:
It was observed that following p38 inhibition, cisplatin resistant HNSCC cells exhibited significant reduction in expression of CSC markers, β-catenin, reduced migration potential and sphere forming ability along with increased apoptotic index demonstrating there was increased sensitivity towards Cisplatin. Molecular docking study identified several interface amino acid residues between p-p38 with CSC markers (Klf4 and CD44). p38 inhibited cisplatin resistant HNSCC cells also exhibited increased DNA damage as measured by Comet assay and γ-H2AX foci formation index. There was significant decrease in DNA repair as confirmed by reduced ERRC1 expression.
Conclusions:
Our study demonstrated that p38 MAPK inhibition can be a targeted approach to overcome resistance in HNSCC thereby escalating the effectiveness of chemotherapy in HNSCC.
Insights
Inhibiting p38 Mitogen-activated protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells overcomes cisplatin resistance. This approach enhances chemotherapy effectiveness by reducing cancer stem cell markers and DNA repair.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Cisplatin resistance is a major challenge in treating head and neck squamous cell carcinoma (HNSCC).
- The role of p38 Mitogen-activated protein kinase (MAPK) in chemoresistance of HNSCC is not fully understood.
- Cancer stem cell (CSC) markers are implicated in HNSCC chemoresistance.
Purpose of the Study:
- To investigate the role of p38 MAPK in cisplatin resistance in HNSCC.
- To determine if inhibiting p38 MAPK can overcome cisplatin resistance in HNSCC.
- To assess the impact of p38 MAPK inhibition on CSC markers and DNA damage/repair in HNSCC.
Main Methods:
- Cisplatin-resistant HNSCC cells were treated with a p38 inhibitor.
- Western blot, RT PCR, and immunohistochemistry were used to analyze protein and gene expression (p-p38, CSC markers).
- Assays for chemoresistance, migration, spheroid formation, DNA damage (Comet assay, γ-H2AX), and DNA repair (ERRC1) were performed.
Main Results:
- p38 inhibition significantly reduced CSC marker expression, migration, and spheroid formation in resistant HNSCC cells.
- Inhibition of p38 MAPK increased HNSCC cell sensitivity to cisplatin, evidenced by increased apoptosis.
- p38 inhibition led to increased DNA damage and decreased DNA repair capacity in cisplatin-resistant HNSCC cells.
Conclusions:
- p38 MAPK plays a crucial role in conferring cisplatin resistance in HNSCC.
- Targeted inhibition of p38 MAPK is a promising strategy to overcome chemoresistance in HNSCC.
- This approach can enhance the efficacy of chemotherapy in HNSCC treatment.
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