Abstract
A recent report (Zhong, D., Xiong, L., Liu, T., Liu, X., Liu, X., Chen, J., Sun, S. Y., Khuri, F. R., Zong, Y., Zhou, Q., and Zhou, W. (2009) J. Biol. Chem. 284, 23225-23233) details that 2-deoxy-D-glucose (2-DG), a well known inhibitor of glycolysis and a candidate antineoplastic agent, also induces insulin-like growth factor 1 receptor (IGF-1R) signaling through the inhibition of insulin-like growth factor 1-insulin-like growth factor-binding protein 3 (IGF-1-IGFBP-3) complex formation. Zhong et al. hypothesized that disrupted IGF-1/IGFBP-3 binding by 2-DG led to increased free IGF-1 concentrations and, consequently, activation of IGF-1R downstream pathways. Because their report suggests unprecedented off-target effects of 2-DG, this has profound implications for the fields of metabolism and oncology. Using ELISA, surface plasmon resonance, and novel "intensity-fading" mass spectrometry, we now provide a detailed characterization of complex formation between IGF-1 and IGFBP-3. All three of these independent methods demonstrated that there was no effect of glucose or 2-DG on the interaction between IGF-1 and IGFBP-3. Furthermore, we show examples of 2-DG exposure associated with reduced rather than increased IGF-1R and AKT activation, providing further evidence against a 2-DG increase in IGF-1R activation by IGF-1-IGFBP-3 complex disruption.
Highlights
Insulin-like growth factors 1 and 2 (IGF-1 and IGF-2) are peptide hormones similar in molecular structure to insulin, and they regulate a variety of cellular activities, including metabolism, proliferation, and growth
Using ELISA, surface plasmon resonance (SPR), and novel “intensity-fading” mass spectrometry (MS), we report that glucose and 2-DG have no effect on IGF-1-insulin-like growth factor-binding proteins (IGFBPs)-3 complex formation
In the presence of excess glucose or 2-DG (25–100 mM), the binding of IGFBP-3 to immobilized IGF-1 was unaltered in all cases
Summary
IGFBP-3 and -5 are the most abundant IGFBPs in the circulation They form a ternary complex with IGFs and a third protein termed acid-labile subunit [7,8,9]. The recent study by Zhong et al [10] showed that 2-DG, apart from its classic activities as an inhibitor of glycolysis, can increase IGF-1R signaling by disrupting IGF-1/IGFBP-3 binding. As increased IGF-1R signaling is associated with greater proliferation of tumor cells, this report has shed doubt on the efficacy of 2-DG as a cancer therapeutic. To examine this issue further, this study characterizes the effect of glucose and 2-DG on binding between IGF-1 and IGFBP-3. Using ELISA, surface plasmon resonance (SPR), and novel “intensity-fading” mass spectrometry (MS), we report that glucose and 2-DG have no effect on IGF-1-IGFBP-3 complex formation
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