♦ See referenced article, J. Biol. Chem. 2014, 289, 29739–29749
Mechanistic target of rapamycin, better known as mTOR, is a kinase that controls cell growth, proliferation, and survival by integrating various extracellular and intracellular signals. mTOR signaling is often up-regulated in various types of cancer. In this Paper of the Week, a team led by Hongbing Zhang at the Chinese Academy of Medical Sciences demonstrated that an enzyme involved in metabolism, pyruvate dehydrogenase kinase 4 (PDK4), regulates signaling carried out by the mTOR complex 1 (mTORC1). The investigators used several cell lines to show that mTORC1 activity increases in the presence of PDK4 and decreases upon suppression of PDK4. The investigators also showed that PDK4 could promote aerobic glycolysis (also called the Warburg effect), a hallmark of cancer, and via regulation of mTORC1, modulate effectors of mTORC1. “The abundance of PDK4 dictated the responsiveness of cells to the mTOR inhibitor, rapamycin,” say the authors. “Combinatory suppression of mTOR and PDK4 exerted synergistic inhibition on cancer cell proliferation.” The authors concluded that PDK4 promoted tumorigenesis by activating one of the signaling pathways of mTORC1.
Schematic illustration of the PDK4-mTORC1 signaling cascade that involves cAMP response element-binding protein and a key activator of mTORC1, Ras homolog enriched in brain (RHEB). PDK4 binds to CREB and prevents its degradation.