The PODNL1/AKT/β-catenin signaling axis mediates glioma progression and sensitivity to temozolomide.

Abnormal expression of small leucine-rich repeat proteins (SLRP) in tumor tissues has been reported as a critical trigger for tumorigenesis and progression. However, the molecular mechanism of PODNL1, a novel member of SLRP family, in glioma remains largely unknown. Therefore, this study aimed to investigate its correlation with clinical factors by glioma cohort and to identify the molecular mechanisms of aberrant PODNL1 gene expression in glioma. Our findings revealed that both PODNL1 mRNA and protein levels were markedly upregulated in glioma tissues, and high PODNL1 mRNA level was significantly associated with poor prognosis of glioma patients. In functional assays, PODNL1 knockdown significantly suppressed the proliferation and invasion abilities of glioma cells, while overexpression of PODNL1 had the opposite effect both in vitro and in vivo. Mechanistically, PODNL1 knockdown suppressed the activation of AKT/mTOR signaling and inhibited nuclear translocation of β-catenin protein in the glioma cells. Our results suggest that PODNL1 acts as an oncogenic factor in glioma by promoting glioma progression through the activation of the kinase AKT, which indeces β-catenin nuclear translocation. Additionally, PODNL1 knockdown enhanced the sensitivity of glioma cells to temozolomide, a chemotherapeutic agent commonly used in the treatment of glioma. The PODNL1/AKT/β-catenin signaling axis represents a new potential therapeutic target against glioma. Furthermore, our data showed the combination of temozolomide and MK-2206, an AKT inhibitor, had a synergistic antitumor effect against glioma cells.