BACKGROUND: Despite standard chemotherapy with temozolomide plus radiotherapy, Glioblastoma (GBM) has a poor median survival of 14 months. LPA was shown be a driver of migration and invasion of glioma. Focal adhesion kinase (FAK) is a 125kDa non-receptor kinase that mediates cell-matrix interaction as well as growth, survival, and migration in cancers. Using an in vitro glioma stem cell (GSC) model, we have previously shown that FAK and phosphorylated FAK is over-expressed and that specific inhibition of FAK by a kinase inhibitor Y15, unlike temozolomide, prevents neurosphere formation and leads to apoptosis. Meanwhile, LPA1 has been shown in our lab to be unregulated in the GSC lines.
Aim: This study examined the involvement of LPA in GSC motility and subsequently the effect of FAK inhibitor Y15 in LPA-induced migration and invasion in primary glioma stem cell lines derived from GBM patients.
Method: 3 different GBM patient derived GSC lines were used. Lactate dehydrogenase assay was employed to determine the cytotoxicity of Y15 on GSC. Cellular migration and invasion were quantified by transwell migration assay and 3D spheroid invasion assay respectively.
Result: GSCs treated with LPA shows dose-dependent enhanced migration with tyrosine phosphorylation of FAK. While treatment with 1,2,4,5-benzenetetraamine-tetrahydrochloride (Y15), a FAK autohophosphorylation inhibitor without LPA does not affect cellular motility, co-treatment of LPA and Y15 reduces GSC’s motility and invasion to a level below the baseline invasion of GSC.
Conclusion: LPA-FAK axis is required in glioma stem cell migration and invasion, serving as a potential therapeutic target in controlling the invasive behavior of glioblastoma.