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WNT signaling modulates chemoresistance to temozolomide in p53-mutant glioblastoma multiforme

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Abstract

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.

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Funding

This work was supported by the Suzhou Science and Technology Development Plan (SYS2020161 to Z.R. Ma, SYS2020151 to Z.H. Zhu and SYS2018072 to Q. Wang), Gusu Health personnel Training program of Suzhou city (GSWS2020050 to S.Z. Cai and GSWS2019017 to X.M. Yan), Clinical key diseases diagnosis and treatment technology projects (LCZX201908 to X.M. Yan).

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Author notes

  1. Zhourui Ma and Shizhong Cai have contributed equally to this work.

Authors and Affiliations

  1. Department of Burns and Plastic Surgery, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, China

    Zhourui Ma, Wei Liu, Zhenhong Zhu & Zhijian Huang

  2. Department of Child and Adolescent Healthcare, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, China

    Shizhong Cai

  3. Department of Urology, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, China

    Qianwei Xiong, Hongliang Xia & Xiangming Yan

  4. Department of Anesthesiology, Children’s Hospital of Soochow University, Suzhou, 215025, Jiangsu, China

    Qian Wang

Authors
  1. Zhourui Ma
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  2. Shizhong Cai
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  3. Qianwei Xiong
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  4. Wei Liu
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  5. Hongliang Xia
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  6. Zhenhong Zhu
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  7. Zhijian Huang
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  8. Xiangming Yan
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  9. Qian Wang
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Contributions

ZM, SC, QX, WL, HX, and ZH, performed the experiments; ZM, SC, ZH and XY, performed data analysis; QW, ZM and SC designed the studies and wrote the manuscript; QW, ZH and XY revised the manuscript.

Corresponding author

Correspondence to Qian Wang.

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Ma, Z., Cai, S., Xiong, Q. et al. WNT signaling modulates chemoresistance to temozolomide in p53-mutant glioblastoma multiforme. Apoptosis 27, 80–89 (2022). https://doi.org/10.1007/s10495-021-01704-x

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  • DOI: https://doi.org/10.1007/s10495-021-01704-x

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