O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma

Cisplatin (CDDP) is an important anti-cancer drug commonly used in various human cancers, including nasopharyngeal carcinoma (NPC). How to overcome the drug resistance of CDDP provides opportunities to improve clinical outcomes of NPC. O-6-methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O-6-alkylguanine alkylating drugs. However, the underlying mechanism and clinical relevance between MGMT and CDDP remain poorly defined in NPC. In this study, we showed that MGMT-proficient cells were highly resistant to the cytotoxic effects of CDDP as compared to MGMT-deficient cells. Further studies showed that the platinum level of DNA after CDDP exposure was significantly lower in MGMT-proficient cells than in MGMT-deficient cells. Host cell reactivation assay revealed that MGMT protected NPC cells from CDDP-induced DNA damage by enhancing DNA repair capacity. Importantly, we demonstrated for the first time that MGMT protein directly bound to CDDP-induced DNA damages. Subsequently, CDDP-bound MGMT protein became ubiquitinated and was degraded through ubiquitin-mediated proteasome system. We further analyzed the relationship between MGMT expression and clinical survivals in a cohort of 83 NPC patients. NPC patients who received CDDP-based concurrent chemoradiotherapy (CCRT), with high MGMT expression level, exhibited shorter progression-free survival (PFS; p=0.022) and overall survival (OS; p=0.015), than patients with low MGMT expression level. Furthermore, high MGMT expression level remained to be an independent prognostic factor for worse PFS (p=0.01, hazard ratio 2.23) and OS (p=0.018, hazard ratio 2.14). Our findings suggest that MGMT protein is important to determine the efficacy of CDDP in NPC. What's new? Although commonly used in human cancers, the efficacy of cisplatin (CDDP) is limited by drug resistance. This study finds the DNA-repair protein O-6-methylguanine-DNA methyltransferase (MGMT) to play an important role in altering the cellular cytotoxicity of CDDP in nasopharyngeal carcinoma cells. Notably, MGMT proteins bind to CDDP-induced DNA damage and are subsequently degraded via the ubiquitin-mediated proteasome system. Furthermore, high MGMT expression predicts shorter prognosis for nasopharyngeal carcinoma patients treated with CDDP-based concurrent chemoradiotherapy. These findings suggest that MGMT is a significant determinant of the efficacy of CDDP and a promising therapeutic target, especially in patients with nasopharyngeal carcinoma.