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Hypoglycemic Agents Increase Regulatory Factor X1 to Inhibit Cancer Cell Behaviour in Human Glioblastoma Cells

Weiran Shan1, Kendrick Zuo2, Zhiyi Zuo1

  • 1Department of Anesthesiology, University of Virginia, Charlottesville, Virginia, USA.

Journal of Cellular and Molecular Medicine
|December 5, 2024
PubMed

Insights

Regulatory factor X1 (RFX1) inhibits glioblastoma growth. Certain diabetes medications, including pioglitazone, increase RFX1 levels, thereby reducing human glioblastoma cell proliferation, migration, and invasion.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Glioblastoma multiforme is an aggressive human brain tumor.
  • Regulatory factor X1 (RFX1) is a transcription factor that suppresses glioblastoma cell proliferation, migration, and invasion.
  • Identifying existing drugs that can enhance RFX1 activity presents a potential therapeutic strategy.

Purpose of the Study:

  • To identify existing medications that upregulate RFX1 in human glioblastoma cells.
  • To evaluate the efficacy of these medications in inhibiting glioblastoma cell behaviors.
  • To elucidate the role of RFX1 in mediating the anti-cancer effects of these drugs.

Main Methods:

  • Bioinformatics analysis was employed to predict medications that increase RFX1 expression.
  • In vitro assays assessed the effects of predicted drugs on glioblastoma cell proliferation, migration, and invasion.
  • Western blotting confirmed RFX1 upregulation.
  • In vivo studies using mouse brain xenografts evaluated tumor growth and cell migration.
  • RFX1-siRNA was used to validate the mechanism of action.

Main Results:

  • Pioglitazone, rosiglitazone, and WY-14643 were identified as potential RFX1-upregulating agents.
  • These agents significantly reduced glioblastoma cell proliferation, migration, and invasion in vitro.
  • The drugs decreased metalloproteinase 2 (MMP2) activity, a key enzyme in tumor invasion.
  • RFX1 knockdown counteracted the inhibitory effects of these drugs, confirming RFX1's crucial role.
  • Pioglitazone demonstrated efficacy in reducing tumor volume and cell migration in a mouse xenograft model.

Conclusions:

  • RFX1 is a validated therapeutic target for glioblastoma treatment.
  • Pioglitazone, rosiglitazone, and WY-14643 exhibit anti-cancer properties against glioblastoma by upregulating RFX1.
  • These findings suggest a potential repurposing of these hypoglycemic agents for glioblastoma therapy.
Keywords:
WY‐14643human glioblastoma cellsmetalloproteinase 2regulatory factor X1thiazolidinediones

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