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 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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1291-1305
Number of pages15
JournalInternational Journal of Cancer
Volume137
Issue number6
DOIs
Publication statusPublished - 2015 Sep 1

Fingerprint

Methyltransferases
Platinum
DNA Repair
DNA
Protein Methyltransferases
Therapeutics
cisplatin-DNA adduct
O-(6)-methylguanine
Nasopharyngeal carcinoma
DNA Damage
Ubiquitinated Proteins
Survival
Chemoradiotherapy
Proteasome Endopeptidase Complex
Ubiquitin
Drug Resistance
Pharmaceutical Preparations
Cisplatin
Disease-Free Survival
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Chen, Shang Hung ; Kuo, Ching Chuan ; Li, Chien Feng ; Cheung, Chun-Hei ; Tsou, Tsui Chun ; Chiang, Huai Chih ; Yang, Yun Ning ; Chang, Shin Lun ; Lin, Li Ching ; Pan, Hsin Yi ; Chang, Kwang Yu ; Chang, Jang-Yang. / O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. In: International Journal of Cancer. 2015 ; Vol. 137, No. 6. pp. 1291-1305.
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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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O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma. / Chen, Shang Hung; Kuo, Ching Chuan; Li, Chien Feng; Cheung, Chun-Hei; Tsou, Tsui Chun; Chiang, Huai Chih; Yang, Yun Ning; Chang, Shin Lun; Lin, Li Ching; Pan, Hsin Yi; Chang, Kwang Yu; Chang, Jang-Yang.

In: International Journal of Cancer, Vol. 137, No. 6, 01.09.2015, p. 1291-1305.

Research output: Contribution to journalArticle

TY - JOUR

T1 - O6-methylguanine DNA methyltransferase repairs platinum-DNA adducts following cisplatin treatment and predicts prognoses of nasopharyngeal carcinoma

AU - Chen, Shang Hung

AU - Kuo, Ching Chuan

AU - Li, Chien Feng

AU - Cheung, Chun-Hei

AU - Tsou, Tsui Chun

AU - Chiang, Huai Chih

AU - Yang, Yun Ning

AU - Chang, Shin Lun

AU - Lin, Li Ching

AU - Pan, Hsin Yi

AU - Chang, Kwang Yu

AU - Chang, Jang-Yang

PY - 2015/9/1

Y1 - 2015/9/1

N2 - 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.

AB - 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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