Heather R. Christofk
Institute for Molecular Medicine
University of California, Los Angeles
Center for Health Sciences 34-115Los Angeles, CA 90095-1735
2010 Searle Scholar
Metabloic Pathways, the Warburg Effect and Cancer
Most cancer cells have a different metabolism than their normal cell counterparts. Known as the Warburg effect (or aerobic glycolysis), this altered metabolism is characterized by enhanced lactate production with reduced oxidative phosphorylation, even in the presence of oxygen. Although this observation was first made over 75 years ago, how cancer cells establish this altered metabolism and whether it is important for tumorigenesis remains unknown. Our research aims to determine the molecular mechanisms by which tumor cells establish and maintain the Warburg effect in cancer, to definitively address whether the Warburg effect is necessary for tumor growth, and to identify novel cancer drug targets responsible for maintenance of the Warburg effect in vivo. Our work will determine whether targeting cancer metabolism is a viable approach for cancer therapy and will better define the role of metabolism for tumor growth.
Virus-mediated changes in cellular metabolism
It has been known since the 1950s that adenovirus infection causes a glycolytic shift in host cell metabolism that closely resembles the Warburg effect in cancer cells. However, the viral elements and cellular machinery involved in this metabolic shift are yet unknown. We are determining the adenoviral genome elements responsible for the glycolytic shift and testing whether this metabolic switch is necessary for virus replication. We have seen a similar metabolic switch upon infection with several different types of viruses, including murine herpes simplex virus, hepatitus c virus, and human cytomegalovirus. We hypothesize that viruses hijack cellular metabolism and cause a shift towards glycolysis to enable use of glucose metabolites for anabolic purposes (i.e. nucleotide, amino acid, and fatty acid biosynthesis) needed for viral replication. Understanding the viral elements responsible for this metabolic shift and the mechanism by which they impact on cellular metabolism may lead to the development of novel anti-viral therapies.
Alternative carbon sources used by non-glycolytic cancers
Most cancer cells undergo a metabolic switch to support proliferation during malignant transformation known as the Warburg effect. The Warburg effect is characterized by increased reliance on glycolysis for glucose metabolism and forms the basis for PET imaging with FDG. For many cancer types, FDG-PET has enabled early detection, staging and restaging, and evaluation of therapeutic interventions. Paradoxically, some aggressive cancers (including pancreatic ductal adenocarcinomas and dedifferentiated liposarcomas) show little or no accelerated glycolysis in patient studies with FDG-PET. These findings imply that increased uptake of carbon sources other than glucose for biomass production may occur. New imaging probes are needed to improve detection, staging, and therapy evaluation for cancers that do not exhibit accelerated glycolysis. Our research aims to determine alternative carbon sources used by these non-glycolytic cancers in order to develop novel imaging probes and treatment strategies.
Connection points between signaling and metabolic pathways
Phosphoproteomic studies in bacteria have shown that over 50% of bacterial phosphorylation events occur on metabolic enzymes. Signaling pathways may have thus initially evolved to regulate metabolism. Interestingly, some of these phosphorylation sites on metabolic enzymes identified in bacteria have also been identified by mass spectrometry in mammals. Since these phosphorylation events are conserved throughout evolution, we hypothesize that they are important connection points for metabolic regulation by signaling pathways. We are currently studying these conserved modification sites and their affect on enzyme activity and metabolic flux.
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