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

Abstract

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 5 0.022) and overall survival (OS; p 5 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 5 0.01, hazard ratio 2.23) and OS (p 5 0.018, hazard ratio 2.14). Our findings suggest that MGMT protein is important to determine the efficacy of CDDP in NPC.

Chemotherapeutic effect of a novel temozolomide analog on nasopharyngeal carcinoma in vitro and in vivo

“…The inability of O6BG to enhance killing by cisplatin was somewhat expected, because the repair effect of MGMT is known to be selective for alkylated O6-guanine [ 7 , 14 , 22 ], and cisplatin rather acts as a DNA crosslinking agent [ 2 ]. However, in contrast to our results, a very recent study by Chen et al [ 3 ] did show that inclusion of O6BG resulted in increased cisplatin cytotoxicity in NPC cell lines HONE-1 and TW1 in vitro. The reasons for this obvious discrepancy are unknown and further studies are needed to resolve this conflicting issue.…”

Periostin overexpression is associated with worse prognosis in nasopharyngeal carcinoma from endemic area: a cohort study

“…The culture conditions of DOK, HONE1, and TW01 cell lines were previously described. 18 Briefly, all cells were maintained in Dulbecco’s Modified Eagle’s Medium (DMEM), supplemented with 10% fetal bovine serum, 100 μg/mL streptomycin, and 100 units/mL penicillin at a 37°C, 5% CO 2 humidified incubator.…”

Differential Expression and Alternative Splicing of Transcripts Associated With Cisplatin-Induced Chemoresistance in Nasopharyngeal Carcinoma

“…Cisplatin (DDP), a DNA damaging agent, exhibits its cytotoxicity and apoptosis-inducing activities by forming DNA adducts or by targeting cancer signaling pathways (Chen et al, 2015;Amable, 2016;Wang et al, 2018). Combinations of DDP-based chemotherapies have been widely used to treat various cancers, including NPC (Agbale et al, 2016;Dugbartey et al, 2016;Sun et al, 2016).…”