GSK-3β regulates tumor growth and angiogenesis in human glioma cells

// Peng Zhao 1, * , Qi Li 2, 4, * , Zhumei Shi 1 , Charlie Li 5 , Lin Wang 2 , Xue Liu 2 , Chengfei Jiang 2, 6 , Xu Qian 2, 6 , Yongping You 1 , Ning Liu 1 , Ling-Zhi Liu 7 , Lianshu Ding 3 , Bing-Hua Jiang 2, 7 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China 2 State Key Lab of Reproductive Medicine, Department of Pathology, and Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing 210029, China 3 Department of Neurosurgery, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an 223300, China 4 Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing, University Medical School, Nanjing 210008, China 5 Department of Environmental Toxicology, University of California-Davis, Davis, CA 94564, USA 6 Ninggao Personalized Medicine and Technology Innovation Center, Nanjing 21130, China 7 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA * These authors have contributed equally to this work Correspondence to: Bing-Hua Jiang, e-mail: binghjiang@hotmail.com Lianshu Ding, e-mail: dlshu@163.com Keywords: GSK-3β, glioma, tumor growth, angiogenesis, mTOR Received: February 16, 2015 Accepted: August 28, 2015 Published: September 10, 2015 ABSTRACT Background: Glioma accounts for the majority of primary malignant brain tumors in adults. Methods: Glioma specimens and normal brain tissues were analyzed for the expression levels of GSK-3β and p-GSK-3β (Ser9) by tissue microarray analysis (TMA) and Western blotting. Glioma cells over-expressing GSK-3β were used to analyze biological functions both in vitro and in vivo . Results: The levels of p-GSK-3β (Ser9), but not total GSK-3β, are significantly up-regulated in glioma tissues compared to normal tissues, and are significantly correlated with the glioma grades. Ectopic expression of GSK-3β decreased the phosphorylation levels of mTOR and p70S6K1; and inhibited β-catenin, HIF-1α and VEGF expression. Forced expression of GSK-3β in glioma cells significantly inhibited both tumor growth and angiogenesis in vivo . Conclusions: These results reveal that GSK-3β regulates mTOR/p70S6K1 signaling pathway and inhibits glioma progression in vivo ; its inactivation via p-GSK-3β (Ser9) is associated with glioma development, which is new mechanism that may be helpful in developing GSK-3β-based treatment of glioma in the future.