The effect of Aldolase C reflects the neurotransmitter secretion and PPARγ signaling in Glioblastoma

Glioblastoma (GBM) are high‐grade gliomas with aggressive progression, poor survival rate, and insufficient therapeutic options. According to molecular characteristics, GBM can be divided into proneural, classical, and mesenchymal subtypes. This study identified that one of the glycolytic enzymes, aldolase C (ALDOC), with the prognostic value could reflect these subtypes' survival rate. In GBM, ALDOC has hypermethylation and loss of expression in tumors, especially mesenchymal subtypes. Interestingly, glycolysis is not affected in the metabolic event, but some brain neurotransmitters (Serotonin) and sugars (inositol) are affected. We confirmed that Serotonin could significantly promote the migration/invasion ability of GBM cells when ALDOC is hypermethylated/loss of function. Mechanistically, Serotonin is excreted to the peripheral area through 5‐hydroxytryptamine receptors (HTRs) family members. We further recruited HTR inhibitors or selective serotonin reuptake inhibitors to reverse such phenotypes. However, due to Serotonin regulating some physiological functions, they may not be appropriate for use. Instead, we analyzed the ALDOC‐based transcriptomics profile and confirmed that the expression of PPARγ is similar to ALDOC in GBM cells. Treating PPARγ agonists can regulate the production of Serotonin and reduce the metastatic state of GBM cells. Additionally, we have observed that the combination of PPARγ agonist and Temozolomide has a synergistic effect that can decrease tumorigenicity and in situ brain tumors. Histological staining demonstrated that the ALDOC and PPARγ signals in the combined group could be rescued. The downstream candidates of PPARγ combined with ALDOC can be applied to the prognostic value of patient survival and various clinicopathological factors. Combining all evidence, we claim that we should pay attention to the importance of the ALDOC‐PPARγ axis and regard it as a novel strategy against GBM.