Cancer cells have enhanced glycolysis and show lower oxygen consumption, indicating a shift to glycolysis for the production of energy, thereby contributing to the metabolic change known as Warburg effect, which is characteristic of virtually all cancers. Many mysteries remain unsolved in our understanding of cancer cell metabolism. Recent discoveries indicate that tumor suppressor p53 has much broader cellular functions, such as regulating glucose metabolism and mitochondrial respiration. We identified GAMT/guanidinoacetate methyltransferase, an enzyme involved in creatine synthesis metabolism as a novel p53 target gene, and a key downstream effector of the adaptive response to DNA damage and nutrient stress in cancer cels. We reveal that GAMT is involved in p53-dependent apoptosis in response to DNA damage/genotoxic stress, and also demonstrate that the GAMT pathway plays an essential role in the regulation of ATP homeostasis during nutrient stress. Surprisingly, we also found that p53->GAMT up-regulates fatty acid oxidation (FAO) induced by DNA damage stress or glucose starvation, facilitating the use of this pathway as an alternative ATP-generating energy source when glucose is scarce. The main goal of this application is to understand the underlying mechanisms for the unusual effect of the p53-GAMT-Creatine pathway in DNA damage-mediated carcinogenesis, as well as in cancer cell metabolism.
The specific aims are to (1) investigate the underlying mechanism(s) for the substitutive effects of the p53-GAMT-Creatine pathway in energy metabolism in cancer cells;(2) define the role of this pathway in regulating DNA damage responses (cell fate decision;cell death or survival) in cancer cells;and (3) determine the function of GAMT in metabolic and DNA damage stress responses using mouse knock-out approaches. Our findings of the p53->GAMT-Creatine pathway represent a new link between cellular stress responses and the metabolic processes of creatine synthesis and FAO, providing implications for understanding selective nutrient adaptation and how this might impact cancer development and responses to conventional therapies. The proposed studies are highly relevant for cancer biology, as they will reveal how metabolic changes impact cancer and how this newly discovered pathway is emerging as a key contributor to tumorigenesis/carcinogenesis.
An aberrant signaling through tumor suppressor p53 is closely associated with various steps of tumorigenesis and carcinogenesis. The proposed studies are highly relevant for cancer biology and etiology, as they will reveal how metabolic changes impact cancer and how a newly discovered pathway of the p53->GAMT->creatine is emerging as a key contributor to tumorigenesis/carcinogenesis.
|Yoon, Kyoung Wan; Byun, Sanguine; Kwon, Eunjeong et al. (2015) Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53. Science 349:1261669|
|Namba, Takushi; Chu, Kiki; Kodama, Rika et al. (2015) Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1Î±/XBP1 pathway. Oncotarget 6:19990-20001|
|Byun, Sanguine; Lim, Semi; Mun, Ji Young et al. (2015) Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways. J Biol Chem 290:23553-62|
|Hiraki, Masatsugu; Hwang, So-Young; Cao, Shugeng et al. (2015) Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis. Chem Biol 22:1206-16|
|Gurkar, Aditi U; Chu, Kiki; Raj, Lakshmi et al. (2013) Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress. Nat Commun 4:2189|
|Mandinova, Anna; Lee, Sam W (2011) The p53 pathway as a target in cancer therapeutics: obstacles and promise. Sci Transl Med 3:64rv1|
|Nishi, Mayuko; Akutsu, Hidenori; Masui, Shinji et al. (2011) A distinct role for Pin1 in the induction and maintenance of pluripotency. J Biol Chem 286:11593-603|
|Ide, Takao; Chu, Kiki; Aaronson, Stuart A et al. (2010) GAMT joins the p53 network: branching into metabolism. Cell Cycle 9:1706-10|
|Carrera, Samantha; de Verdier, Petra J; Khan, Zahid et al. (2010) Protection of cells in physiological oxygen tensions against DNA damage-induced apoptosis. J Biol Chem 285:13658-65|