title: PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma.
abstract: Accumulating evidence has shown that PI3K/Akt pathway is frequently hyperactivated in osteosarcoma (OS) and contributes to tumor initiation and progression. Altered phenotype of glucose metabolism is a key hallmark of cancer cells including OS. However, the relationship between PI3K/Akt pathway and glucose metabolism in OS remains largely unexplored. In this study, we showed that elevated Hexokinase-2 (HK2) expression, which catalyzes the first essential step of glucose metabolism by conversion of glucose into glucose-6-phosphate, was induced by activated PI3K/Akt signaling. Immunohistochemical analysis showed that HK2 was overexpressed in 83.3% (25/30) specimens detected and was closely correlated with Ki67, a cell proliferation index. Silencing of endogenous HK2 resulted in decreased aerobic glycolysis as demonstrated by reduced glucose consumption and lactate production. Inhibition of PI3K/Akt signaling also suppressed aerobic glycolysis and this effect can be reversed by reintroduction of HK2. Furthermore, knockdown of HK2 led to increased cell apoptosis and reduced ability of colony formation; meanwhile, these effects were blocked by 2-Deoxy-d-glucose (2-DG), a glycolysis inhibitor through its actions on hexokinase, indicating that HK2 functions in cell apoptosis and growth were mediated by altered aerobic glycolysis. Taken together, our study reveals a novel relationship between PI3K/Akt signaling and aerobic glycolysis and indicates that PI3K/Akt/HK2 might be potential therapeutic approaches for OS.
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Baobiao
authors.initials: B
authors.lastname: Zhuo
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Zhengwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Haihui
authors.initials: H
authors.lastname: Qin
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Qingzeng
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Fengfei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Surgery, The Children's Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006, PR China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Ultrasonography, Afﬁliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province 221006, PR China. Electronic address: wangrong2008163@163.com.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
mesh_terms: D017209:Apoptosis; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology*; D002648:Child; D006593:Hexokinase / Q000378:metabolism*; D006801:Humans; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D006593:Hexokinase; D051057:Proto-Oncogene Proteins c-akt
keywords: Growth; Hexokinase-2; PI3K/Akt signaling; Pediatric osteosarcoma