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Notch1 and Major Vault Proteins Modulate Temozolomide Resistance in Glioblastoma

Cengiz Tuncer1, Ceyhan Hacioglu2,3

  • 1Faculty of Medicine, Department of Neurosurgery, Düzce University, Düzce, Turkey.

Journal of Cellular and Molecular Medicine
|March 18, 2025
PubMed

Insights

Targeting Notch1 in glioblastoma multiforme (GBM) can overcome temozolomide (TMZ) resistance. Inhibiting Notch1 reduces proliferation and resensitizes GBM cells to TMZ by downregulating resistance proteins like MVP, MGMT, and ABCG2.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioblastoma multiforme (GBM) is an aggressive brain tumor with significant challenges in chemotherapy resistance.
  • The Notch signalling pathway is implicated in promoting tumor proliferation in GBM cells.
  • Temozolomide (TMZ) is a standard chemotherapy agent for GBM, but resistance is a major obstacle.

Purpose of the Study:

  • To investigate the role of Notch1 in temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) cells.
  • To evaluate the potential of targeting the Notch signalling pathway as a therapeutic strategy for GBM.
  • To determine the effect of Notch1 inhibition on chemoresistance-associated proteins and cell proliferation.

Main Methods:

  • Generation of temozolomide (TMZ)-resistant glioblastoma multiforme (GBM) cell lines (U87-R and U251-R).
  • Investigation of Notch1 expression and its effect on resistance proteins: major vault protein (MVP), O6-methylguanine-DNA-methyltransferase (MGMT), and ATP-binding-cassette transporter-G2 (ABCG2).
  • Utilized siRNA to downregulate Notch-1 expression and assessed its impact on cell proliferation and chemosensitivity.

Main Results:

  • TMZ-resistant GBM cells exhibited increased expression of MVP, MGMT, and ABCG2, correlating with reduced TMZ sensitivity.
  • TMZ-resistant GBM cells showed higher proliferation rates compared to parental cells.
  • Downregulation of Notch-1 significantly inhibited proliferation of TMZ-resistant GBM cells.
  • Notch-1 inhibition led to the inactivation of MGMT, ABCG2, and MVP, increasing sensitivity to TMZ, particularly through MVP downregulation.

Conclusions:

  • Notch1 plays a crucial role in promoting proliferation and chemoresistance in glioblastoma multiforme (GBM).
  • Targeting Notch1, especially by downregulating MVP, presents a promising therapeutic strategy to overcome temozolomide (TMZ) resistance in GBM.
  • Inhibiting Notch1 may restore chemosensitivity by targeting MVP, MGMT, and ABCG2 in GBM cells.
Keywords:
glioblastoma multiformemajor vault proteinnotchtemozolomide

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