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ADAM12 promotes temozolomide resistance in glioblastoma by activating the TNF-α - NF-κB pathway

Chunchao Cheng1, Longtao Cui1, Xiaoteng Cui1

  • 1Laboratory of Neuro-Oncology, Tianjin Neurological Institute, Department of Neurosurgery, Tianjin Medical University General Hospital and Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin, 300052, China; Tianjin Medical University General Hospital, Tianjin, 300052, China.

Cancer Letters
|April 3, 2025
PubMed

Insights

Targeting ADAM12 protein can overcome temozolomide (TMZ) resistance in glioma. Inhibiting ADAM12 sensitizes glioma cells to TMZ by blocking the TNF-α/NF-κB pathway, offering a new therapeutic strategy.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Temozolomide (TMZ) resistance is a major challenge in glioma treatment, linked to NF-κB phosphorylation.
  • ADAM12 is overexpressed in glioma and its role in TMZ resistance is unclear.

Purpose of the Study:

  • To investigate the role of ADAM12 in the development of TMZ resistance in glioma.
  • To explore ADAM12 as a potential therapeutic target to overcome TMZ resistance.

Main Methods:

  • ADAM12 knockdown in glioma cell lines and in vivo models.
  • ELISA and docking simulations to identify ADAM12's function.
  • Analysis of the TNF-α/NF-κB pathway and MGMT expression.

Main Results:

  • ADAM12 knockdown inhibited cell cycle, enhanced apoptosis, and sensitized glioma cells to TMZ.
  • ADAM12 promotes glioma progression via TNF-α shedding.
  • Targeting ADAM12 in vivo increased TMZ sensitivity.
  • ADAM12 is a prognostic marker for TMZ treatment.
  • ADAM12 knockdown sensitized cells with unmethylated MGMT to TMZ by inhibiting the TNF-α/NF-κB pathway and reducing MGMT.

Conclusions:

  • ADAM12 drives TMZ resistance in glioma by shedding TNF-α.
  • Targeting ADAM12 is a promising strategy to overcome TMZ resistance in glioma, particularly in tumors with unmethylated MGMT.
Keywords:
ADAM12DNA damage responseGBMTMZTNF-α

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