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Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin

  • Authors:
    • Datong Sun
    • Shenghui Yang
    • Xufeng Zhang
    • Sai Li
    • Lin Wang
    • Junmin Chen
    • Chun Qiu
    • Ke Xu
  • View Affiliations / Copyright

    Affiliations: Department of Oncology, Hainan Provincial People's Hospital, Haikou, Hainan 571101, P.R. China, Department of Stomatology, First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China, Clinical Immunology Section, School of Tropical Medicine and Laboratory Medicine, Hainan Medical University, Haikou, Hainan 571199, P.R. China
    Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 328
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    Published online on: February 25, 2021
       https://doi.org/10.3892/ol.2021.12580
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Abstract

Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. GBM is currently treated with temozolomide (TMZ), although patients often exhibit resistance to this agent. Although several mechanisms underlying the resistance of GBM to TMZ have been identified, the combination of these mechanisms is not sufficient to fully account for this phenomenon. Our previous study demonstrated that knocking down the Forkhead box protein O3a (FoxO3a) gene, a member of the FoxO subfamily of transcription factors, resulted in glioma cell sensitization to TMZ, accompanied by reduced levels of nuclear β‑catenin. The aim of the present study was to specify how FoxO3a and β‑catenin are implicated in glioma cell TMZ resistance. Using the U87 and U251 parental cell lines (also designated as sensitive cell lines) and corresponding resistant cell lines (U87‑TR and U251‑TR, generated by repeated TMZ treatments), coupled with a combined knockdown/overexpression strategy, it was revealed that FoxO3a or β‑catenin overexpression in TMZ‑treated U87 and U251 cells markedly increased cellular proliferation; co‑expression of both FoxO3a and β‑catenin resulted in the highest increase. Knockdown of either FoxO3a or β‑catenin in U87‑TR and U251‑TR cells led to a significant decrease in cell viability, which was rescued by the re‑expression of FoxO3a in FoxO3a‑knockdown cells. Subsequent experiments demonstrated that, in U87‑TR and U251‑TR cells, FoxO3a knockdown significantly reduced the protein levels of matrix metallopeptidase (MMP)9, while overexpression of FoxO3a in U87 and U251 cells enhanced the nuclear accumulation of β‑catenin, concomitantly with an increase in MMP9 levels. Furthermore, MMP9 knockdown markedly reduced the levels of nuclear β‑catenin. Collectively, the findings of the present study suggest that FoxO3a may regulate the nuclear accumulation of β‑catenin by modulating MMP9 expression, thereby rendering glioblastoma cells resistant to TMZ, and may provide unique molecular insights into the mechanisms underlying the development of TMZ resistance in GBM.
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Copy and paste a formatted citation
Spandidos Publications style
Sun D, Yang S, Zhang X, Li S, Wang L, Chen J, Qiu C and Xu K: Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin. Oncol Lett 21: 328, 2021.
APA
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J. ... Xu, K. (2021). Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin. Oncology Letters, 21, 328. https://doi.org/10.3892/ol.2021.12580
MLA
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J., Qiu, C., Xu, K."Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin". Oncology Letters 21.4 (2021): 328.
Chicago
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J., Qiu, C., Xu, K."Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin". Oncology Letters 21, no. 4 (2021): 328. https://doi.org/10.3892/ol.2021.12580
Copy and paste a formatted citation
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Spandidos Publications style
Sun D, Yang S, Zhang X, Li S, Wang L, Chen J, Qiu C and Xu K: Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin. Oncol Lett 21: 328, 2021.
APA
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J. ... Xu, K. (2021). Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin. Oncology Letters, 21, 328. https://doi.org/10.3892/ol.2021.12580
MLA
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J., Qiu, C., Xu, K."Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin". Oncology Letters 21.4 (2021): 328.
Chicago
Sun, D., Yang, S., Zhang, X., Li, S., Wang, L., Chen, J., Qiu, C., Xu, K."Forkhead box protein O3a promotes glioma cell resistance to temozolomide by regulating matrix metallopeptidase and β‑catenin". Oncology Letters 21, no. 4 (2021): 328. https://doi.org/10.3892/ol.2021.12580
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