Inhibition of CD44 sensitizes cisplatin-resistance and affects Wnt/β-catenin signaling in HNSCC cells

CD44 is one of the key cancer stem-like cell (CSC) marker and may have a potential role in tumorigenesis. In this study, we investigated the role of CD44 in prognosis of HNSCC patients, its possible crosstalk with Wnt/β-catenin signaling and modulating cisplatin resistance. We observed increased expression of CD44 in the cut margin of recurrent HNSCC patients were associated with poor prognosis. We observed that inhibition of CD44 by using 1,2,3,4 tetrahydroisoquinoline (THIQ) modulates the expression of Wnt/ β-catenin signaling proteins and further silencing of β-catenin also decreases the expression of CD44. This led us to investigate the possible protein-protein interaction between CD44 and β-catenin. Co-immunoprecipitation study illustrated possible interaction between CD44 and β-catenin which was further confirmed by molecular docking and molecular dynamic (MD) simulation studies. Molecular docking study revealed that one interface amino acid residue Glu642 of β -catenin interacts with Lys92 of CD44 which was also present for 20% of simulation time. Furthermore, we observed that inhibition of CD44 chemosensitizes cisplatin-resistant HNSCC cells towards cisplatin. In conclusion, this study investigated the possible role of CD44 along with Wnt/ β-catenin signaling and their possible therapeutic role to abrogate cisplatin resistance.