2-Deoxyglucose induces Akt phosphorylation via a mechanism independent of LKB1/AMP-activated protein kinase signaling activation or glycolysis inhibition.
The compound 2-deoxyglucose (2-DG) enhances chemotherapy/radiotherapy in cell lines and animal models, prompting two phase I clinical trials with this cancer therapeutic. Although its mechanism of action has not been fully elucidated, it is hypothesized that the molecular basis of 2-DG activity is related to glycolysis inhibition. Here, we report that 2-DG induced Akt phosphorylation at Thr(308) and Ser(473) as early as 15 min post-treatment. These phosphorylation events required phosphatidylinositol-3-kinase activity but were not related to LKB1/AMP-activated protein kinase signaling, the inhibition of glycolysis or epidermal growth factor receptor signaling. The 2-DG-mediated Akt phosphorylation also led to the phosphorylation of Akt downstream targets, such as Foxo3a, GSK3beta, and Chk1. Because the functional consequence of Akt activation includes chemotherapy/radiotherapy resistance, our data suggested that the combination of phosphatidylinositol-3-kinase/Akt inhibitory agents in 2-DG-based chemotherapy/radiotherapy may result in enhanced therapeutic efficacy.
Zhong
Diansheng
D
The Winship Cancer Institute, Emory University School of Medicine, Building C, Room 4084, 1365 Clifton Road Northeast, Atlanta, GA 30322, USA.
Liu
Xiuju
X
Schafer-Hales
Katherine
K
Marcus
Adam I
AI
Khuri
Fadlo R
FR
Sun
Shi-Yong
SY
Zhou
Wei
W
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000963:Antimetabolites / Q000494:pharmacology*; D015153:Blotting, Western; D000071877:Checkpoint Kinase 1; D003847:Deoxyglucose / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate; D000963:Antimetabolites; D000071877:Checkpoint Kinase 1; D003847:Deoxyglucose; D066246:ErbB Receptors; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008156:Luciferases; D009097:Multienzyme Complexes; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; C499517:FOXO3 protein, human; C512478:EGFR protein, human; C000605867:CHEK1 protein, human; C000605506:GSK3B protein, human; C109790:STK11 protein, human