Podocalyxin Promotes Glioblastoma Multiforme Cell Invasion and Proliferation via β-Catenin Signaling

Both podocalyxin (PODX) and beta-catenin (beta-cat) signaling reportedly play important roles in glioblastoma multiforme (GBM) progression. In this study, we for the first time explored crosstalk between PODX and beta-cat signaling in GBM cells, and assessed its impact on GBM cell invasion and proliferation. Stable overexpression of PODX in LN-229 and U-118 MG human GBM cells increased the soluble/intracellular beta-cat level, TOPflash luciferase reporter activity, the mRNA levels of beta-cat signaling target genes, matrix metalloproteinase 9 (MMP9) expression/activity, and cell invasion and proliferation, which was abolished by selective p38 mitogen-activated protein kinase (MAPK) inhibitor PD169316 and selective beta-cat signaling inhibitor CCT031374. On the other hand, stable knockdown of PODX in LN-229 and U-118 MG cells decreased the soluble beta-cat level, TOPflash luciferase reporter activity, the mRNA levels of beta-cat signaling target genes, MMP9 expression/activity, and cell invasion and proliferation, which was completely reversed by overexpression of a constitutively active beta-cat mutant. In addition, overexpression of PODX induced p38 MAPK activity and inactivating phosphorylation of glycogen synthase kinase-3 beta (GSK-3 beta) at serine 389 in LN-229 and U-118 MG cells, which was abolished by PD169316, but not CCT031374; knockdown of PODX decreased p38 MAPK activity and inactivating phosphorylation of GSK-3 beta at serine 389 in both cell lines, which was not significantly affected by overexpression of constitutively active beta-cat. In conclusion, this study indicates that PODX promotes GBM cell invasion and proliferation by elevating the soluble beta-cat level/beta-cat signaling through the p38 MAPK/GSK-3 beta pathway. Uncovering the PODX/beta-cat signaling axis adds new insights not only into the biological functions of PODX and beta-cat, but also into the molecular mechanisms underlying GBM progression.