The Glycolytic Inhibitor 2-Deoxyglucose Activates Multiple Prosurvival Pathways through IGF1R

• Type of Material: Article
• Authors: Diansheng Zhong, Tianjin Medical University; Li Xiong, Emory University; Tongrui Liu, Emory University; Xiuju Liu, Emory University; Xiangguo Liu, Emory University; Jing Chen, Emory University; Shi-Yong Sun, Emory University; Fadlo Khuri, Emory University; Yaping Zong, Full Moon Biosystems, Inc.; Qinghua Zhou, Tianjin Medical University; Wei Zhou, Emory University
• Language: English
• Date: 2009-08-28
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://www.jbc.org/content/284/35/23225
• Title of Journal or Parent Work: Journal of Biological Chemistry
• Volume: 284
• Issue: 35
• Start Page: 23225
• End Page: 23233
• Grant/Funding Information: This work was supported, in whole or part, by National Institutes of Health Grants PO1 CA116676-030002 (to W. Z.) and RO1 CA118470-01 (to S.-Y. S.) from NCI.
• Research Categories: Health Sciences, Oncology

Abstract

Recent molecular studies indicate that aerobic glycolysis plays an important role in tumorigenesis and is a valid target for cancer therapy. Although 2-deoxyglucose (2-DG) is well characterized as a glycolytic inhibitor, we recently discovered that it activates a prosurvival oncoprotein, AKT, through PI3K. In this study, we discovered that 2-DG treatments disrupted the binding between insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP3) so that the free form of IGF-1 could be released from the IGF-1·IGFBP3 complex to activate IGF-1 receptor (IGF1R) signaling. Because IGF1R signaling is involved, PI3K/AKT constitutes only one of the prosurvival pathways that are activated by 2-DG treatment; we validated that MEK-ERK signaling was also induced in an IGF1R-dependent manner in some cancer cell lines. Furthermore, our phospho-specific antibody microarray analysis indicated that 2-DG up-regulated the phosphorylation of 64 sites within various signaling pathways in H460 cells. Chemical inhibition of IGF1R reduced 57 of these up-regulations. These data suggest that 2-DG-induced activation of many survival pathways can be jointly attenuated through IGF1R inhibition. Our in vitro analysis demonstrated that treatment with a combination of subtoxic doses of 2-DG and the IGF1R inhibitor II reduced cancer cell proliferation 90% and promoted significant apoptosis.