Research Papers:
Overexpression of Gαi3 in human glioma is required for AktmTOR activation and cell growth
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Zheng-wei Li1,*, Shang Cai2,*, Yuanyuan Liu3,*, Chuan-lai Yang3,*, Ye Tian2, Gang Chen4, C. Cao3
1Surgical Department I, Xuzhou Children's Hospital, Xuzhou, China
2Department of Radiotherapy and Oncology, the Second Affiliated Hospital of Soochow University, Suzhou, China
3Institute of Neuroscience, Soochow University, Suzhou, China
4Department of Neurosurgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
*Co-first authors
Correspondence to:
Ye Tian, email: [email protected], [email protected]
Gang Chen, email: [email protected]
C. Cao, email: [email protected]
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.