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FoxM1-mediated RFC5 expression promotes temozolomide resistance

Wan-Xin Peng1, Xiu Han1, Chun-Li Zhang1

  • 1School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, China.

Cell Biology and Toxicology
|February 11, 2017
PubMed

Insights

Forkhead box M1 (FoxM1) drives temozolomide (TMZ) resistance in glioma by activating DNA repair gene RFC5, independent of MGMT. Inhibiting FoxM1 with thiostrepton may overcome this resistance.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Genetics

Background:

  • Methylguanine-DNA-methyltransferase (MGMT) is crucial for temozolomide (TMZ) resistance in glioma, but many MGMT-inactivated gliomas remain resistant.
  • The mechanisms underlying this persistent TMZ resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of forkhead box M1 (FoxM1) in mediating TMZ resistance in glioma, independent of MGMT.
  • To explore the potential of targeting the FoxM1 pathway for overcoming TMZ resistance.

Main Methods:

  • Correlation analysis of FoxM1 and RFC5 expression in human glioma cells.
  • Investigation of FoxM1's transcriptional activity on the RFC5 promoter.
  • Assessment of the effects of FoxM1 and RFC5 knockdown on TMZ sensitivity.
  • Evaluation of thiostrepton, a FoxM1 inhibitor, in combination with TMZ in glioma cells.

Main Results:

  • FoxM1 expression positively correlates with RFC5 expression in human glioma cells.
  • FoxM1 directly activates RFC5 expression via its promoter.
  • Knockdown of FoxM1 or RFC5 partially restores sensitivity to TMZ.
  • The combination of thiostrepton and TMZ significantly inhibits glioma cell proliferation and induces apoptosis.

Conclusions:

  • The FoxM1-RFC5 axis represents a novel mechanism contributing to TMZ resistance in glioma, independent of MGMT.
  • Targeting FoxM1 with thiostrepton offers a potential therapeutic strategy to overcome TMZ resistance in glioma.
Keywords:
Chemo-resistanceFoxM1GliomaRFC5TMZ

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