title: O(6) -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 = 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.
authors.affiliation: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Division of Hematology/Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Shang Hung
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Ching Chuan
authors.initials: CC
authors.lastname: Kuo
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan.|Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan.
authors.forename: Chien Feng
authors.initials: CF
authors.lastname: Li
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chun Hei Antonio
authors.initials: CH
authors.lastname: Cheung
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Tsui Chun
authors.initials: TC
authors.lastname: Tsou
authors.affiliation: Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Huai Chih
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan.
authors.forename: Yun Ning
authors.initials: YN
authors.lastname: Yang
authors.affiliation: Department of Otolaryngology, Chi-Mei Medical Center, Tainan, Taiwan.
authors.forename: Shin Lun
authors.initials: SL
authors.lastname: Chang
authors.affiliation: Department of Radiation Oncology, Chi-Mei Medical Center, Tainan, Taiwan.|School of Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Li Ching
authors.initials: LC
authors.lastname: Lin
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Chi-Mei Medical Center, Liouying, Tainan, Taiwan.
authors.forename: Hsin Yi
authors.initials: HY
authors.lastname: Pan
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Kwang Yu
authors.initials: KY
authors.lastname: Chang
authors.affiliation: Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.|Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.|Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Jang Yang
authors.initials: JY
authors.lastname: Chang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002277:Carcinoma; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D018736:DNA Adducts / Q000187:drug effects* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D018572:Disease-Free Survival; D006801:Humans; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D011379:Prognosis
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin
keywords: MGMT; chemoradiotherapy; cisplatin; drug resistance; nasopharyngeal carcinoma