Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of pharmaceutical analysis, 2024-06, Vol.14 (6), p.100950-15, Article 100950

Ort / Verlag

China: Elsevier B.V

Erscheinungsjahr

2024

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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-methyltransferase (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 sensitivity 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. [Display omitted] •The expression of MGMT positively correlates with DDP tolerance in CRC.•Activation of the Wnt pathway stimulates MGMT expression in CRC.•Degradation of CDK1 by MGMT induces slow cycling cells.•MGMT recruits XRCC6 to restore nonhomologous end joining.