Wang_2021_Theranostics_11_8535

Neuroligin-3 (NLGN3) is necessary and sufficient to promote glioma cell growth. The recruitment of Galphai1/3 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 Galphai1/3 in NLGN3-driven glioma cell growth. Results: NLGN3-induced Akt-mTORC1 and Erk activation was inhibited by decreasing Galphai1/3 expression. In contrast ectopic Galphai1/3 overexpression enhanced NLGN3-induced signaling. In glioma cells, NLGN3-induced cell growth, proliferation and migration were attenuated by Galphai1/3 depletion with shRNA, but facilitated with Galphai1/3 overexpression. Significantly, Galphai1/3 silencing inhibited orthotopic growth of patient-derived glioma xenografts in mouse brain, whereas forced Galphai1/3-overexpression in primary glioma xenografts significantly enhanced growth. The growth of brain-metastatic human lung cancer cells in mouse brain was largely inhibited with Galphai1/3 silencing. It was however expedited with ectopic Galphai1/3 overexpression. In human glioma Galphai3 upregulation was detected, correlating with poor prognosis. Conclusion: Galphai1/3 mediation of NLGN3-induced signaling is essential for neuronal-driven glioma growth.