2IN - PI 3-Kinase and Cancer Metabolism

Abstract

ABSTRACT Phosphoinositide 3-kinase (PI 3-Kinase) generates phosphatidylinositol-3,4,5-trisphosphate (PIP3) at the plasma membrane in response to stimulation of cells with growth factors and hormones. This lipid recruits certain signal transduction proteins to the membrane, initializing cellular signaling cascades that control glucose uptake, cell metabolism, protein synthesis and cell growth. A central mediator of PI 3-Kinase signaling is the protein-Ser/Thr kinase, AKT. Over the past six years signaling networks downstream of AKT have been elucidated that regulate protein synthesis and glucose metabolism, in part via activation of mTOR. Importantly, we have found that while growth factor receptors enhance glucose uptake and glucose metabolism, they decrease the activity of pyruvate kinase, the last step in the pathway. Our studies indicate that the inhibition of pyruvate kinase allows cells to divert intermediates in glycolysis into pathways for synthesis of DNA, RNA, proteins and lipids that are needed for cell growth. Disclosure Dr. Cantley is a founder and member of the BOD of Agios Pharmaceuticals, a company that targets metabolic enzymes for treating cancer. Dr. Cantley consults for Novartis and GSK, companies developing drugs that target PI3K.