Glycogen Synthase Kinase 3α and 3β Mediate a Glucose-Sensitive Antiapoptotic Signaling Pathway To Stabilize Mcl-1

Abstract

Glucose uptake and utilization are growth factor-stimulated processes that are frequently upregulated in cancer cells and that correlate with enhanced cell survival. The mechanism of metabolic protection from apoptosis, however, has been unclear. Here we identify a novel signaling pathway initiated by glucose catabolism that inhibited apoptotic death of growth factor-deprived cells. We show that increased glucose metabolism protected cells against the proapoptotic Bcl-2 family protein Bim and attenuated degradation of the antiapoptotic Bcl-2 family protein Mcl-1. Maintenance of Mcl-1 was critical for this protection, as glucose metabolism failed to protect Mcl-1-deficient cells from apoptosis. Increased glucose metabolism stabilized Mcl-1 in both cell lines and primary lymphocytes via inhibitory phosphorylation of glycogen synthase kinase 3α and 3β (GSK-3α/β), which otherwise promoted Mcl-1 degradation. While a number of kinases can phosphorylate and inhibit GSK-3α/β, we provide evidence that protein kinase C may be stimulated by glucose-induced alterations in diacylglycerol levels or distribution to phosphorylate GSK-3α/β, maintain Mcl-1 levels, and inhibit cell death. These data provide a novel nutrient-sensitive mechanism linking glucose metabolism and Bcl-2 family proteins via GSK-3 that may promote survival of cells with high rates of glucose utilization, such as growth factor-stimulated or cancerous cells.

We thank Sally Kornbluth (Duke University), Christopher Newgard (Duke University), Leta Nutt (Duke University), David R. Plas (University of Cincinatti), W. Kimryn Rathmell (University of North Carolina at Chapel Hill), Dennis Thiele (Duke University), Craig B. Thompson (University of Pennsylvania), and Tso-Pang Yao (Duke University) for helpful comments. We thank the Sarah W. Stedman Center for Nutrition and Metabolism for technical assistance. Glut1-transgenic mice were a generous gift of Craig Thompson and the Abramson Family Cancer Research Institute (University of Pennsylvania). We are grateful for reagents provided by H. J. Brady (University College, London), D. Turner (University of Michigan), M. Spitaler and D. Cantrell (University of Dundee), M. Ehlers (Duke University), U. Maurer (Institut für Molekulare Medizin und Zellforschung), and D. Green (St. Jude Children's Research Hospital).

This work was funded by a Howard Temin KO1 Career Development Award from the National Cancer Institute (to J.C.R.), a Sidney Kimmel Foundation for Cancer Research Scholar Award (to J.C.R.), a V Foundation for Cancer Research Scholar Award (to J.C.R.), and R01 AI063345 (to J.C.R.).