We propose to determine the molecular basis underlying the Warburg effect of cancer cells, which are commonly observed metabolic properties of cancer cells playing important roles for the growth of tumor. Currently several cancer-enriched isoforms of metabolic enzymes are known to be required for the Warburg effect and for the growth of cancer cells in stress conditions. However, it is still unclear how these cancer-specific metabolic enzymes contribute to the growth of tumor. We are interested in cellular metabolites regulating these enzymes in an isozyme-specific manner because it will provide researchers a clue to understand the molecular basis underlying cancer cell metabolism. In particular, we are interested in a cellular metabolite called SAICAR, which is an intermediate of de novo purine nucleotide biosynthesis. Our preliminary data indicate that (1) SACIAR isozyme-selectively stimulates pyruvate kinase M2 (PKM2), one of a few metabolic enzymes found to be required for tumor growth in xenograft experiments and for the growth of cancer cells in stress conditions;(2) this interaction induces the Warburg effect and (3) promotes cancer cell survival in nutrient-limited conditions. This interaction of SAICAR and PKM2 is a distinct feature of cancer cells observed in many types of cancer cells but not in normal cells tested. We propose to study following three specific aims: (1) Test additional conditions relevant to tumor micro-environments to determine the importance of this interaction in cancer, (2) Define the molecular mechanism upstream of the accumulation of SAICAR, and (3) testing whether this SAICAR-PKM2 interaction has lasting impacts on cancer cells by analyzing the role of SAICAR in the regulation of PKM2's nuclear functions. From these studies, we expect to provide clues on the molecular basis connecting the Warburg effect and PKM2 to cell growth and proliferation.
Metabolic abnormalities of cancer cells, including elevated glucose uptake and oxygen-independent fermentation, are essential for the growth of cancer cells in stress conditions. However, it is still unclear how these metabolic abnormalities contribute to cancer cell growth and proliferation at molecular level. This project investigates th molecular basis of the metabolic abnormalities by focusing on a cellular metabolite specifically regulating a metabolic isozyme enriched in cancer cells and required for the metabolic abnormalities.
|Yan, Ming; Chakravarthy, Srinivas; Tokuda, Joshua M et al. (2016) Succinyl-5-aminoimidazole-4-carboxamide-1-ribose 5'-Phosphate (SAICAR) Activates Pyruvate Kinase Isoform M2 (PKM2) in Its Dimeric Form. Biochemistry 55:4731-6|
|Keller, Kirstie E; Doctor, Zainab M; Dwyer, Zachary W et al. (2014) SAICAR induces protein kinase activity of PKM2 that is necessary for sustained proliferative signaling of cancer cells. Mol Cell 53:700-9|