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Multiple Pathway-Dephosphorylated ASK-1 Confers Temozolomide-Resistance to Human Glioma Cells

Kai Gao1, Kun She, Jie Fan

  • 1Affiliated Hospital of Hebei University of Engineering, Department of Neurosurgery I, Handan 056002, Hebei, China.

Turkish Neurosurgery
|March 23, 2023
PubMed
Abstract

Insights

Dephosphorylation of ASK-1 (Apoptosis Signal-regulating Kinase 1) induces Temozolomide (TMZ) resistance in glioma cells. Upstream suppressors like Thioredoxin (Trx) are involved in this resistance mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Glioblastoma is an aggressive brain tumor with limited treatment options.
  • Temozolomide (TMZ) is a standard chemotherapy agent for glioma.
  • Acquired resistance to TMZ remains a significant clinical challenge.

Purpose of the Study:

  • To investigate the role of ASK-1 (Apoptosis Signal-regulating Kinase 1) in the development of TMZ resistance in glioma.
  • To identify the underlying molecular mechanisms and modulators involved in ASK-1-mediated TMZ resistance.

Main Methods:

  • Assessed ASK-1 phosphorylation, IC50, cell viability, and apoptosis in parental and TMZ-resistant glioma cell lines (U87, U251, U87-TR, U251-TR).
  • Utilized an ASK-1 inhibitor (selonsertib) and overexpression of ASK-1 upstream modulators (Trx, PP5, 14-3-3, Cdc25C) to block ASK-1 function.
  • Evaluated the impact of ASK-1 modulation on TMZ sensitivity and resistance phenotypes.

Main Results:

  • TMZ-resistant cells exhibited higher IC50, survival, and lower apoptosis post-TMZ treatment.
  • ASK-1 phosphorylation was reduced in TMZ-resistant cells compared to sensitive cells upon TMZ challenge.
  • Inhibition of ASK-1 (selonsertib) or overexpression of upstream suppressors (Trx, PP5, 14-3-3, Cdc25C) led to ASK-1 dephosphorylation and induced a TMZ-resistant phenotype.
  • ASK-1 dephosphorylation correlated with increased IC50, cell survival, and reduced apoptosis.

Conclusions:

  • Dephosphorylation of ASK-1 is a key event that confers TMZ resistance in human glioma cells.
  • ASK-1 upstream suppressors, including Thioredoxin (Trx), protein phosphatase 5 (PP5), 14-3-3, and cell division cycle 25C (Cdc25C), play a crucial role in mediating this resistance.
  • Targeting ASK-1 dephosphorylation or its upstream modulators may offer novel therapeutic strategies for overcoming TMZ resistance in glioma.

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