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

Shang Hung Chen, Ching Chuan Kuo, Chien Feng Li, Chun Hei Antonio Cheung, Tsui Chun Tsou, Huai Chih Chiang, Yun Ning Yang, Shin Lun Chang, Li Ching Lin, Hsin Yi Pan, Kwang Yu Chang, Jang Yang Chang

研究成果: Article

13 引文 斯高帕斯(Scopus)

摘要

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. O6-methylguanine-DNA methyltransferase (MGMT) has been well-characterized to be a therapeutic determinant of O6-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.

原文English
頁(從 - 到)1291-1305
頁數15
期刊International Journal of Cancer
137
發行號6
DOIs
出版狀態Published - 2015 九月 1

    指紋

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

引用此