首页|MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

MGMT activated by Wnt pathway promotes cisplatin tolerance through inducing slow-cycling cells and nonhomologous end joining in colorectal cancer

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  • 国家科技期刊平台
  • NETL
  • NSTL
  • 万方数据
Chemotherapy resistance plays a pivotal role in the prognosis and therapeutic failure of patients with colorectal cancer(CRC).Cisplatin(DDP)-resistant cells exhibit an inherent ability to evade the toxic chemotherapeutic drug effects which are characterized by the activation of slow-cycle programs and DNA repair.Among the elements that lead to DDP resistance,O6-methylguanine(O6-MG)-DNA-meth-yltransferase(MGMT),a DNA-repair enzyme,performs a quintessential role.In this study,we clarify the significant involvement of MGMT in conferring DDP resistance in CRC,elucidating the underlying mechanism of the regulatory actions of MGMT.A notable upregulation of MGMT in DDP-resistant cancer cells was found in our study,and MGMT repression amplifies the sensitivity of these cells to DDP treatment in vitro and in vivo.Conversely,in cancer cells,MGMT overexpression abolishes their sensi-tivity to DDP treatment.Mechanistically,the interaction between MGMT and cyclin dependent kinase 1(CDK1)inducing slow-cycling cells is attainted via the promotion of ubiquitination degradation of CDK1.Meanwhile,to achieve nonhomologous end joining,MGMT interacts with XRCC6 to resist chemotherapy drugs.Our transcriptome data from samples of 88 patients with CRC suggest that MGMT expression is co-related with the Wnt signaling pathway activation,and several Wnt inhibitors can repress drug-resistant cells.In summary,our results point out that MGMT is a potential therapeutic target and predictive marker of chemoresistance in CRC.

Colorectal cancerMGMTChemotherapy resistanceSlow-cycling cellsNonhomologous end joiningWnt pathway

Haowei Zhang、Qixin Li、Xiaolong Guo、Hong Wu、Chenhao Hu、Gaixia Liu、Tianyu Yu、Xiake Hu、Quanpeng Qiu、Gang Guo、Junjun She、Yinnan Chen

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Department of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China

Center for Gut Microbiome Research,Med-X Institute,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China

Department of General Surgery,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710061,China

Department of High Talent,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an,710061,China

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2024

10.1016/j.jpha.2024.02.004

药物分析学报(英文)
西安交通大学

药物分析学报(英文)

影响因子：0.244
ISSN：2095-1779
年,卷(期)：2024.14(6)