Over-expression of Gαi3 in human glioma is required for Akt-mTOR activation and cell growth

Abstract

// Zheng-wei Li 1, * , Shang Cai 2, * , Yuanyuan Liu 3, * , Chuan-lai Yang 3, * , Ye Tian 2 , Gang Chen 4 , C. Cao 3 1 Surgical Department I, Xuzhou Children's Hospital, Xuzhou, China 2 Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China 3 Institute of Neuroscience, Soochow University, Suzhou, China 4 Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China * Co-first authors Correspondence to: Ye Tian, email: tianyesuzhoua163@163.com , dryetian@126.com Gang Chen, email: nju_neurosurgery@163.com C. Cao, email: caocong@suda.edu.cn Keywords: glioma, gαi3, receptor tyrosine kinase, Akt-mTOR, signalings Received: June 13, 2016      Accepted: July 19, 2016      Published: August 01, 2016 ABSTRACT We have previously identified an unique function of G protein α inhibitory subunit (Gαi protein) in transducing Akt-mTOR signaling. Here, we examined the expression and biological functions of Gαi protein 3 (Gαi3) in human glioma. As compared to the normal brain tissues, mRNA and protein expressions of Gαi3 were significantly upregulated in multiple human glioma tissues. Its expression level was associated with receptor tyrosine kinases (RTKs, including EGFR, FGFR and PDGFRα) over-expression and Akt-mTOR hyperactivity. Gαi3 formed a complex with above RTKs and the adaptor protein Gab1 in glioma tissues and cells, which was required for downstream Akt-mTOR activation. Gαi3 shRNA knockdown or dominant negative mutation largely attenuated Akt-mTOR activation and glioma cell growth. Further, Gαi3-knockout (KO) mouse embryonic fibroblasts (MEFs) showed decreased Akt activation and cell growth. Reversely, introduction of a constitutively-active Gαi3 in glioma cells enhanced Akt-mTOR activation and cell growth. In vivo , Gαi3 shRNA-expressing U87MG tumors grew slower than the control shRNA-bearing U87MG tumors in nude mice. Akt-mTOR activation was also inhibited in U87MG tumors with Gαi3 shRNA. Collectively, these results indicate that over-expressed Gαi3 forms a complex with several RTKs in human glioma to transduce Akt-mTOR activation and tumor cell growth.