Friday, October 25, 2013 - 2:00pm
Fung Auditorium | Powell-Focht Bioengineering Hall
Professor, Tumor Microenvironment Program
Sanford/Burnham Medical Research Institute
Metabolic Reprogramming and Sensing in Cancer by the Autophagy Adaptor p62
How cells respond to changes in nutrient availability is critical for an adequate control of metabolic homeostasis. mTORC1 is a central complex kinase in these processes. The signaling adaptor p62 binds raptor, an integral component of the mTORC1 pathway. p62 interacts with TRAF6 and is required for mTORC1 translocation to the lysosome and its subsequent activation. Here we show that TRAF6 is recruited to and activates mTORC1 through p62 in amino acid stimulated cells. We also show that TRAF6 is necessary for the translocation of mTORC1 to the lysosomes and that the TRAF6- catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids. TRAF6, through its interaction with p62 and activation of mTORC1, modulates autophagy and is an important mediator in cancer cell proliferation. Interfering with the p62-TRAF6 interaction serves to modulate autophagy and nutrient sensing. In addition, tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.
Dr. Moscat earned a bachelor’s degree in chemistry and a doctorate in biochemistry/molecular biology at the Universidad Complutense in Madrid, Spain. He completed postgraduate studies with fellowships of the Spanish Education and Science Ministry and Juan March Foundation in Madrid and at the NIH. Dr. Moscat joined the University of Cincinnati in 2006 from the Center of Molecular Biology of the Spanish National Research Council in Madrid, where he conducted cancer cell biology research, focusing primarily on signaling pathways in cancer, obesity and inflammation. In 2008, he became professor and chairman of the Department of Cancer and Cell Biology at the University of Cincinnati College of Medicine and associate director of basic science for the Cincinnati Cancer Consortium. Dr. Moscat joined the Sanford-Burnham faculty in 2011.