PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression

Yu Chan Chang*, Ming Hsien Chan, Chien Hsiu Li, Chi Long Chen, Wen Chiuan Tsai, Michael Hsiao

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastoma (GBM) is a type of brain cancer categorized as a high-grade glioma. GBM is characterized by limited treatment options, low patient survival rates, and abnormal serotonin metabolism. Previous studies have investigated the tumor suppressor function of aldolase C (ALDOC), a glycolytic enzyme in GBM. However, it is unclear how ALDOC regulates production of serotonin and its associated receptors, HTRs. In this study, we analyzed ALDOC mRNA levels and methylation status using sequencing data and in silico datasets. Furthermore, we investigated pathways, phenotypes, and drug effects using cell and mouse models. Our results suggest that loss of ALDOC function in GBM promotes tumor cell invasion and migration. We observed that hypermethylation, which results in loss of ALDOC expression, is associated with serotonin hypersecretion and the inhibition of PPAR-γ signaling. Using several omics datasets, we present evidence that ALDOC regulates serotonin levels and safeguards PPAR-γ against serotonin metabolism mediated by 5-HT, which leads to a reduction in PPAR-γ expression. PPAR-γ activation inhibits serotonin release by HTR and diminishes GBM tumor growth in our cellular and animal models. Importantly, research has demonstrated that PPAR-γ agonists prolong animal survival rates and increase the efficacy of temozolomide in an orthotopic brain model of GBM. The relationship and function of the ALDOC-PPAR-γ axis could serve as a potential prognostic indicator. Furthermore, PPAR-γ agonists offer a new treatment alternative for glioblastoma multiforme (GBM).

Original languageEnglish
Article number266
JournalCell Communication and Signaling
Volume22
Issue number1
DOIs
StatePublished - Dec 2024

Keywords

  • 5-Hydroxytryptamine receptors
  • Aldolase C
  • Glioblastoma
  • PPAR-γ
  • Serotonin

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