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Cell Biology and Toxicology

, Volume 33, Issue 6, pp 527–537 | Cite as

FoxM1-mediated RFC5 expression promotes temozolomide resistance

  • Wan-xin Peng
  • Xiu Han
  • Chun-li Zhang
  • Lu Ge
  • Feng-yi Du
  • Jie Jin
  • Ai-hua Gong
Original Article

Abstract

Although methylguanine-DNA-methyltransferase (MGMT) plays an important role in resistance to temozolomide (TMZ) in glioma, 40% of gliomas with MGMT inactivation are still resistant to TMZ. The underlying mechanism is not clear. Here, we report that forkhead box M1 (FoxM1) transcriptionally activates the expression of DNA repair gene replication factor C5 (RFC5) to promote TMZ resistance in glioma cells independent of MGMT activation. We showed that RFC5 expression is positively correlated with FoxM1 expression in human glioma cells and FoxM1 is able to transcriptionally activate RFC expression by interaction with the RFC5 promoter. Furthermore, knockdown of FoxM1 or RFC5 partially re-sensitizes glioma cells to TMZ. Consistently, thiostrepton, a FoxM1 inhibitor, in combination with TMZ significantly inhibits proliferation and promotes apoptosis in glioma cells. Taken together, these findings suggest that the FoxM1-RFC5 axis may mediate TMZ resistance and thiostrepton may serve as a potential therapeutic agent against TMZ resistance in glioma cells.

Keywords

Glioma Chemo-resistance FoxM1 RFC5 TMZ 

Abbreviations

FoxM1

Forkhead box M1

MGMT

Methylguanine-DNA methyltransferase

TMZ

Temozolomide

RFC

Replication factor C

Notes

Acknowledgements

This work was supported by grants from the Natural Science Foundation of China (81372718 to A.G.; 31100964 to W.P.), Postdoctoral Science Foundation Funded Project by Jiangsu province (1402102C to W.P.), and the Specialized Research Fund for Senior Personnel Program of Jiangsu University (10JDG45 to W.P.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of the interest.

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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  • Wan-xin Peng
    • 1
  • Xiu Han
    • 1
  • Chun-li Zhang
    • 1
  • Lu Ge
    • 2
  • Feng-yi Du
    • 1
  • Jie Jin
    • 1
  • Ai-hua Gong
    • 1
  1. 1.School of MedicineJiangsu UniversityZhenjiangChina
  2. 2.Department of GastroenterologyAffiliated Hospital of Jiangsu UniversityZhenjiangChina

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