P63-Mediated Cisplatin Resistance with Head and Neck Cancer

Abstract

Objective: 1) Understand the molecular pathway of cisplatin-based chemoresistance with head and neck cancer. 2) Investigate if p63 plays an important role in regulating MRE11/RAD50/NBS1 (MRN) complex that contributes to cisplatin-based chemoresistance.

Method: Both JHU006 and JHU020 HNSCC cell lines were characterized as either sensitive or resistant to cisplatin. MRN and p63 expression levels were examined. The p63-mediated MRN regulation was studied by introducing mutant NBS1 and siRNA. Cell growth was evaluated in response to cisplatin treatment and regulation of p63 and MRN.

Results: IC50 to cisplatin for JHU006 and JHU020 was 8.76 and 0.61, respectively, suggesting that JHU006 is a cisplatin-resistant cell line. Increased expression levels of MRN were found after cisplatin treatment in JHU006 as compared with JHU020. The p63 expression level, which is a positive transcriptional factor for RAD50 and MRE11, was up-regulated after cisplatin treatment in JHU006 but not in JHU020. The knockdown of p63 resulted in the down-regulation of MRN, and therefore there were interrupted DNA repair and sensitized resistant tumor cells to cisplatin. The introduction of mutant NBS1 could down-regulate MRN, but was not effective on the p63 expression.

Conclusion: Our study suggested that p63 may play an important role in regulating cisplatin-based chemoresistance via MRN. The understanding of the molecular pathway of cisplatin-based chemoresistance could help us to design an efficient treatment strategy for head and neck cancer.