O6‐methylguanine DNA methyltransferase repairs platinum‐DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma |
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| Authors: | 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 |
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| Affiliation: | 1. National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan;2. Department of Pathology, Chi‐Mei Medical Center, Tainan, Taiwan;3. Department of Medical Technology, Chung Hwa University of Medical Technology, Tainan, Taiwan;4. Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan;5. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan;6. Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan;7. Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Taiwan;8. Department of Otolaryngology, Chi‐Mei Medical Center, Tainan, Taiwan;9. Department of Radiation Oncology, Chi‐Mei Medical Center, Tainan, Taiwan;10. School of Medicine, Taipei Medical University, Taipei, Taiwan;11. Division of Hematology/Oncology, Department of Internal Medicine, Chi‐Mei Medical Center, Liouying, Tainan, Taiwan;12. Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan;13. Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan;14. Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan |
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| 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. 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. |
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| Keywords: | MGMT cisplatin drug resistance chemoradiotherapy nasopharyngeal carcinoma |
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