Diagnostic Significance of p38 Isoforms (p38α, p38β, p38γ, p38δ) in Head and Neck Squamous Cell Carcinoma: Comparative Serum Level Evaluation and Design of Novel Peptide Inhibitor Targeting the Same

Purpose The p38 mitogen-activated protein kinase (MAPKs) play a crucial role in the production of pro-inflammatory cytokines and over-expression of it increase cytokines which promote cancer. Among four isoforms, p38 alpha has been well studied in head and neck squamous cell carcinoma (HNSCC) and other cancers as a therapeutic target p38 delta has recently emerged as a potential disease-specific drug target. Elevated serum p38 alpha level in HNSCC was reported earlier from our lab. This study aims to estimate the levels of p38 MAPK-isoforms in the serum of HNSCC and design peptide inhibitor targeting the same. Materials and Methods Levels of p38 MAPK isoforms in the serum of HNSCC and healthy controls were quantified by surface plasmon resonance technology. The peptide inhibitor for p38 MAPK was designed by molecular modeling using Grid-based Ligand Docking with Energetics tools and compared with known specific inhibitors. Results We have observed highly elevated levels of all four isoforms of p38 MAPK in serum of HNSCC patients compared to the control group. Further, serum p38 alpha, p38 beta, and p38 delta levels were down regulated after therapy in follow-up patients, while p38 gamma showed no response to the therapy. Present study screened designed peptide WFYH as a specific inhibitor against p38 delta. The specific inhibitor of p38 delta was found to have no effect on p38 alpha due to great structural difference at ATP binding pocket. Conclusion In this study, first time estimated the levels of p38 MAPK isoforms in the serum of HNSCC. It can be concluded that p38 MAPK isoforms can be a diagnostic and prognostic marker for HNSCC and p38 delta as a therapeutic target.