Jonathan M. Ghergurovich
Princeton University
CancerInternal medicineEndocrinologyCitric acid cycleEnzymeRespirationChemistryGlycolysisAsparagineT cellDehydrogenaseSerineMitochondrial biogenesisEssential amino acidAsparaginaseGlutamineSerine hydroxymethyltransferaseExtracellularMitochondrionPentose phosphate pathwayProtein biosynthesisCancer researchNucleotideAmino acidBiosynthesisBiochemistryCell growthMetabolismNAD+ kinaseBiologyCell biologyCatabolismCytosol
18Publications
11H-index
1,180Citations
Publications 17
Newest
#1Jonathan M. Ghergurovich (Princeton University)H-Index: 11
#2Jessica D. Lang (TGen: Translational Genomics Research Institute)H-Index: 5
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 19 authors...
Summary Background Upregulated glucose metabolism is a common feature of tumors. Glucose can be broken down by either glycolysis or the oxidative pentose phosphate pathway (oxPPP). The relative usage within tumors of these catabolic pathways remains unclear. Similarly, the extent to which tumors make biomass precursors from glucose, versus take them up from the circulation, is incompletely defined. Methods We explore human triple-negative breast cancer (TNBC) metabolism by isotope tracing with [...
3 CitationsSource
#1Juan Carlos García-Cañaveras (Princeton University)H-Index: 15
#2Olga Lancho (RU: Rutgers University)H-Index: 2
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 11 authors...
Folate metabolism enables cell growth by providing one-carbon (1C) units for nucleotide biosynthesis. The 1C units are carried by tetrahydrofolate, whose production by the enzyme dihydrofolate reductase is targeted by the important anticancer drug methotrexate. 1C units come largely from serine catabolism by the enzyme serine hydroxymethyltransferase (SHMT), whose mitochondrial isoform is strongly upregulated in cancer. Here we report the SHMT inhibitor SHIN2 and demonstrate its in vivo target e...
21 CitationsSource
#1Yang Zhang (UPenn: University of Pennsylvania)H-Index: 4
#2Yi Xu (UPenn: University of Pennsylvania)H-Index: 2
Last. Xiaolu Yang (UPenn: University of Pennsylvania)H-Index: 39
view all 8 authors...
Summary The emergence of cancer from diverse normal tissues has long been rationalized to represent a common set of fundamental processes. However, these processes are not fully defined. Here, we show that forced expression of glucose-6-phosphate dehydrogenase (G6PD) affords immortalized mouse and human cells anchorage-independent growth in vitro and tumorigenicity in animals. Mechanistically, G6PD augments the NADPH pool by stimulating NAD+ kinase-mediated NADP+ biosynthesis in addition to conv...
8 CitationsSource
#1Jonathan M. Ghergurovich (Princeton University)H-Index: 11
#2Mark Esposito (Princeton University)H-Index: 9
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 10 authors...
The enzyme glucose-6-phosphate dehydrogenase (G6PD) is a major contributor to NADPH production and redox homeostasis and its expression is upregulated and correlated with negative patient outcomes in multiple human cancer types. Despite these associations, whether G6PD is essential for tumor initiation, growth, or metastasis remains unclear. Here we employ modern genetic tools to evaluate the role of G6PD in lung, breast, and colon cancer driven by oncogenic K-Ras. Human HCT116 colorectal cancer...
5 CitationsSource
#1Joshua Z. Wang (Princeton University)H-Index: 1
#2Jonathan M. Ghergurovich (Princeton University)H-Index: 11
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 4 authors...
Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyltetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that methionine synthase is only a minor source of methionine in cell culture, tissues, or xenografted tumors. In...
Source
#1Lifeng Yang (Princeton University)H-Index: 18
#2Juan Carlos Garcia Canaveras (Princeton University)H-Index: 2
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 17 authors...
Summary NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine cat...
46 CitationsSource
#1Jonathan M. Ghergurovich (Princeton University)H-Index: 11
#2Joyce O'Shaughnessy (Baylor University Medical Center)H-Index: 66
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 7 authors...
Triple negative breast cancer (TNBC) is an aggressive tumor type for which few targeted treatments exist. Altered tumor metabolism may provide novel diagnostic and therapeutic opportunities. Recent genetic analyses in TNBC demonstrate augmented expression of pathways related to glucose metabolism, including glycolysis, the pentose phosphate (PPP), and serine biosynthetic pathways. No studies, however, have directly probed how glucose is utilized by TNBCs in vivo. Here, we trace these metabolic f...
Source
#1Jonathan M. Ghergurovich (Princeton University)H-Index: 11
#2Juan Carlos García-Cañaveras (Princeton University)H-Index: 15
Last. Joshua D. Rabinowitz (Princeton University)H-Index: 100
view all 16 authors...
Glucose is catabolized by two fundamental pathways, glycolysis to make ATP and the oxidative pentose phosphate pathway to make reduced nicotinamide adenine dinucleotide phosphate (NADPH). The first step of the oxidative pentose phosphate pathway is catalyzed by the enzyme glucose-6-phosphate dehydrogenase (G6PD). Here we develop metabolite reporter and deuterium tracer assays to monitor cellular G6PD activity. Using these, we show that the most widely cited G6PD antagonist, dehydroepiandosterone...
20 CitationsSource
#1Noga Ron-Harel (Harvard University)H-Index: 13
#2Jonathan M. Ghergurovich (Princeton University)H-Index: 11
Last. Marcia C. Haigis (Harvard University)H-Index: 60
view all 8 authors...
Summary T cell stimulation is metabolically demanding. To exit quiescence, T cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is ...
46 CitationsSource
#1David PropperH-Index: 27
#2Haiyong Han (TGen: Translational Genomics Research Institute)H-Index: 39
Last. Gerard I. EvanH-Index: 102
view all 19 authors...
BackgroundTriptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer c...
4 CitationsSource