WNT signaling modulates chemoresistance to temozolomide in p53-mutant glioblastoma multiforme
| Autor: | Zhourui, Ma, Shizhong, Cai, Qianwei, Xiong, Wei, Liu, Hongliang, Xia, Zhenhong, Zhu, Zhijian, Huang, Xiangming, Yan, Qian, Wang |
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| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
Cancer Research Brain Neoplasms Biochemistry (medical) Clinical Biochemistry Pharmaceutical Science Apoptosis Cell Biology Mice Drug Resistance Neoplasm Cell Line Tumor Temozolomide Animals Humans Neoplasm Recurrence Local Tumor Suppressor Protein p53 Glioblastoma Antineoplastic Agents Alkylating Wnt Signaling Pathway |
| Zdroj: | Apoptosis. 27:80-89 |
| ISSN: | 1573-675X 1360-8185 |
| Popis: | Glioblastoma multiforme (GBM) has been characterized by the high incidence, therapy tolerance and relapse. The molecular events controlling GBM resistant to chemotherapy temozolomide (TMZ) remain to be elusive. Here, we identified WNT signaling was amplified by TMZ and mediated drug response in GBM. We found O6-methylguanine DNA methyltransferase (MGMT) was redundant to WNT-mediated chemoresistance, which was highly associated with p53 mutation status. In GBM with p53 mutation, loss of function of p53 downregulated miR-34a expression, which represses transcription of WNT ligand 6 (WNT6) by directly binding to 3' UTR of WNT6 mRNA, leading to activation of WNT signaling, and the eventual WNT-mediated chemoresistance to TMZ. Combined treatment of TMZ with WNT inhibitor or miR34a mimic induced drug sensitivity of p53-mutant GBM cells and extended survival in xenograft mice in vivo. Our findings provide insight into understanding the molecular mechanism of GBM chemoresistance to TMZ and facilitating to develop novel treatment strategy to combat p53-mutant GBM by targeting miR-34a/WNT6 axis. |
| Databáze: | OpenAIRE |
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