P38 Mitogen-activated protein kinase modulates cisplatin resistance in Head and Neck Squamous Cell Carcinoma cells. (February 2021)

• Record Type: Journal Article
• Authors: Roy, Shomereeta; Roy, Souvick; Anuja, Kumari; Thakur, Shweta; Akhter, Yusuf; Padhi, Swatishree; Banerjee, Birendranath
• Is Part Of: Archives of oral biology. Volume 122(2021)
• Publication Date: 2021-02
• Subjects: HNSCC -- p38 MAPK -- resistance -- CSCs -- β-catenin -- cisplatin -- DNA damage; Mouth -- Periodicals; Mouth -- Diseases -- Periodicals; Dentistry -- Periodicals; Electronic journals; 617.6005
• DOI: 10.1016/j.archoralbio.2020.104981
• Languages: English
• ISSNs: 0003-9969

Abstract

Highlights: p38 MAPK modulates Wnt/β-catenin signaling in cisplatin resistant HNSCC cells. p38 inhibition attenuates CSC marker expression in cisplatin resistant HNSCC cells. In-silico studies revealed possible molecular interactions of p-p38 and CSC markers. p38 inhibition sensitizes cisplatin resistant HNSCC cells to cisplatin. p38 inhibition hampers DNA repair efficiency of cisplatin resistant HNSCC cells. Abstract: 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-H2 AX 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.