Neuronal-Driven Glioma Growth Requires G Alpha I1 And G Alpha I3

Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of G alpha i1/3 to the ligand-activated receptor tyrosine kinases (RTKs) is essential for mediating oncogenic signaling.Methods: Various genetic strategies were utilized to examine the requirement of G alpha i1/3 in NLGN3-driven glioma cell growth.Results: NLGN3-induced Akt-mTORC1 and Erk activation was inhibited by decreasing G alpha i1/3 expression. In contrast ectopic G alpha i1/3 overexpression enhanced NLGN3-induced signaling. In glioma cells, NLGN3-induced cell growth, proliferation and migration were attenuated by G alpha i1/3 depletion with shRNA, but facilitated with G alpha i1/3 overexpression. Significantly, G alpha i1/3 silencing inhibited orthotopic growth of patient-derived glioma xenografts in mouse brain, whereas forced G alpha i1/3-overexpression in primary glioma xenografts significantly enhanced growth. The growth of brain-metastatic human lung cancer cells in mouse brain was largely inhibited with G alpha i1/3 silencing. It was however expedited with ectopic G alpha i1/3 overexpression. In human glioma G alpha i3 upregulation was detected, correlating with poor prognosis.Conclusion: G alpha i1/3 mediation of NLGN3-induced signaling is essential for neuronal-driven glioma growth.