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Forkhead box O1 targeting replication factor C subunit 2 expression promotes glioma temozolomide resistance and

Xingsheng Qiu1, Guifeng Tan2, Hao Wen2

  • 1Department of Radiation Oncology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Annals of Translational Medicine
|May 14, 2021
PubMed
Abstract

Insights

Forkhead box O1 (FoxO1) and replicator C2 (RFC2) drive temozolomide resistance in gliomas by regulating DNA repair. Targeting the FoxO1/RFC2 pathway offers a potential therapeutic strategy for resistant gliomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Temozolomide (TMZ) resistance is a significant challenge in glioma treatment.
  • The precise mechanisms underlying TMZ resistance in gliomas are not fully understood.
  • This study investigates a novel DNA repair pathway involving forkhead box O1 (FoxO1) and replicator C2 (RFC2) in glioma resistance.

Purpose of the Study:

  • To identify and characterize a new DNA repair mechanism contributing to temozolomide (TMZ) resistance in gliomas.
  • To elucidate the roles of forkhead box O1 (FoxO1) and replicator C2 (RFC2) in TMZ resistance.
  • To evaluate the FoxO1/RFC2 signaling pathway as a potential therapeutic target for TMZ-resistant gliomas.

Main Methods:

  • Established a TMZ-resistant glioma cell line (U87R) through continuous TMZ exposure.
  • Assessed cell proliferation using CCK8 and colony formation assays.
  • Detected epithelial-mesenchymal transition (EMT) markers via Western blot.
  • Analyzed the association between FoxO1 and RFC2 expression using heat maps and scatter plots.
  • Quantified gene and protein expression levels using qRT-PCR and Western blotting.
  • Investigated the transcriptional regulation of RFC2 by FoxO1 using luciferase reporter gene assays.
  • Examined the impact of FoxO1/RFC2 knockdown (using shRNA) on cell proliferation, TMZ resistance, and apoptosis (via flow cytometry and immunoblotting).

Main Results:

  • The U87R cell line exhibited significantly increased levels of FoxO1 and RFC2 proteins.
  • FoxO1 and RFC2 expression showed a positive correlation in glioma tissues.
  • FoxO1 was identified as a key regulator of RFC2 expression, acting as a transcriptional activator by binding to the RFC2 promoter.
  • Knockdown of FoxO1 or RFC2 significantly reduced cell proliferation, enhanced TMZ sensitivity, and induced apoptosis in U87R cells.

Conclusions:

  • The FoxO1/RFC2 signaling pathway plays a crucial role in promoting glioma cell proliferation and resistance to temozolomide.
  • Targeting the FoxO1/RFC2 pathway presents a promising therapeutic strategy for overcoming TMZ resistance in glioma patients.
Keywords:
Gliomaforkhead box O1 (FoxO1)replication factor C2 (RFC2)temozolomide (TMZ)

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