The Emerging Hallmarks of Cancer Metabolism

In the paper

“Tumorigenesis is dependent on the reprogramming of cellular metabolism as both direct and indirect consequence of oncogenic mutations.”

In the paper

“In such a manner, intracellular glutamine may facilitate the import of a broad range of LAT1 substrates, including leucine, isoleucine, valine, methionine, tyrosine, tryptophan and phenylalanine”

What the sources say

• Not checked yetcites Yanagida et al., 2001 source

In the paper

“when deprived of growth factors, hematopoietic and neuronal cells fail to consume glucose in quantities sufficient to even maintain cellular bioenergetics”

What the sources say

• Not checked yetcites Lindsten et al., 2003 source
• Not checked yetcites Rathmell et al., 2000 source

In the paper

“the optimal growth of cultured HeLa cells requires a 10- to a 100-fold molar excess of glutamine in culture medium relative to other amino acids”

What the sources say

• Not checked yetcites Eagle, 1955 source

In the paper

“Thus, glutamine provides the nitrogen required for the biosynthesis of purine and pyrimidine nucleotides, glucosamine-6-phosphate, as well as non-essential amino acids.”

In the paper

“glutamine was found to be the most rapidly consumed amino acid by Ehrlich ascites carcinomas as well as by a number of hepatomas and carcinosarcomas proliferating in vivo”

What the sources say

• Not checked yetcites Marquez et al., 1989 source
• Not checked yetcites Sauer et al., 1982

In the paper

“Glutamine, a second principal growth-supporting substrate contributes not only carbon, but also reduced nitrogen for the de novo biosynthesis of a number of diverse nitrogen-containing compounds.”

In the paper

“numerous tumorigenic contexts are associated with the depletion of glutamine from the tumor environment as compared to the corresponding normal tissue”

What the sources say

• Not checked yetcites Marquez et al., 1989 source
• Not checked yetcites Rivera et al., 1988 source
• Not checked yetcites Roberts and Frankel, 1949

In the paper

“The alterations in intracellular and extracellular metabolites that can accompany cancer-associated metabolic reprogramming have profound effects on gene expression, cellular differentiation and the tumor microenvironment.”

In the paper

“Through the catabolism of glucose and glutamine, a cell maintains pools of diverse carbon intermediates, which are utilized as building blocks for the assembly of various macromolecules.”

In the paper

“the import of an essential amino acid leucine through the plasma membrane-localized neutral amino acid antiporter LAT1 was shown to be coupled to a simultaneous efflux of glutamine”

What the sources say

• Not checked yetcites Nicklin et al., 2009 source

In the paper

“A markedly increased consumption of glucose by tumors in comparison to the non-proliferating normal tissues was first described more than 90 years ago by the German physiologist Otto Warburg”

What the sources say

• Not checked yetcites Warburg O, 1924
• Not checked yetcites Warburg et al., 1927 source

In the paper

“survival of growth-factor deprived cells can be readily restored by a combined expression of a plasma membrane glucose transporter GLUT1 and the first enzyme of the glycolytic pathway hexokinase (HK)”

What the sources say

• Not checked yetcites Rathmell et al., 2003 source

In the paper

“A common feature of cancer cell metabolism is the ability to acquire necessary nutrients from a frequently nutrient-poor environment and utilize these nutrients to both maintain viability and build new biomass.”

In the paper

“The reprogramming of carbon metabolism by proliferating cells provides part of the explanation for Warburg’s original observations concerning cancer metabolism.”

In the paper

“targeted depletion of mitochondrial DNA reduces the tumorigenic potential of cancer cell lines in vitro and in vivo”

What the sources say

• Not checked yetcites Cavalli et al., 1997
• Not checked yetcites Morais et al., 1994
• Not checked yetcites Tan et al., 2015 source

In the paper

“The major use of reduced carbon in proliferating cells is for the biosynthesis of a diverse array of biomolecules – among which are fatty acids and cholesterol, pentose and hexose sugar derivatives, glycerol, nucleotides and non-essential amino acids.”

In the paper

“aberrantly activated oncogenes and/or loss of tumor suppressors can lock cancer cells in a state where they constitutively scavenge available glucose, glutamine and essential amino acids from the extracellular environment, which, in turn, enables their uncontrolled proliferation.”

In the paper

“expression of mutant Ras or c-Src alleles provides cells with a mechanism that allows them to recover free amino acids through the lysosomal degradation of extracellular proteins”

What the sources say

• Not checked yetcites Commisso et al., 2013 source

In the paper

“A second consequence of a lack of vascular nutrient delivery in growing tumors is an emergence of hypoxic areas, which leads to a suppression of a number of biosynthetic reactions that require molecular oxygen as an electron acceptor.”

In the paper

“cancer cells accumulate oncogenic alterations that convey to them a significant degree of independence from these external requirements”

What the sources say

• Not checked yetcites Hanahan and Weinberg, 2000 source
• Not checked yetcites Vogelstein and Kinzler, 2004

In the paper

“proliferating cells have only a modest increase in their consumption of ATP relative to their need for precursor molecules and reducing equivalents in the form of NADPH.”

In the paper

“Taken together, these observations suggest that the influx of glucose into cells is not driven by the immediate bioenergetic needs of a cell, but on the contrary, is rationed strictly as a result of extracellular stimuli.”

In the paper

“Warburg demonstrated that despite consuming massive amounts of glucose and being exposed to ambient oxygen, cancer cells did not take advantage of the bioenergetic benefits offered by the coupling of glycolysis to the TCA cycle. On the contrary, when grown in glucose-rich medium, any cells converted the surplus pyruvate to lactate, which, in turn, was secreted into the extracellular environment.”

In the paper

“TCA cycle activity which generates NADH and ATP is the major negative regulator of glucose metabolism.”

In the paper

“Albumin supplementation has even been shown to restore the proliferation of a KRASG12D-driven mouse pancreatic cancer line in the culture medium that was devoid of all free amino acids”

What the sources say

• Not checked yetcites Kamphorst et al., 2015 source

In the paper

“upregulation of a long chain fatty acid-binding protein FABP4 on the surface of metastatic ovarian cancer cells allows them to acquire fatty acids directly from the adipocytes of the omental fat”

What the sources say

• Not checked yetcites Nieman et al., 2011 source

In the paper

“deletion of a core component of the autophagy machinery, Atg7, was shown to dramatically change the nature of lung tumors driven by KrasG12D and BrafV600E oncogenes from malignant adenocarcinomas to benign oncocytomas”

What the sources say

• Not checked yetcites Guo et al., 2013 source
• Not checked yetcites Strohecker et al., 2013 source

In the paper

“preferential conversion of glucose into lactate has been later demonstrated in genetically normal proliferating cells, as well as in cells infected by viruses”

What the sources say

• Not checked yetcites Brand et al., 1986 source
• Not checked yetcites Chambers et al., 2010 source
• Not checked yetcites Noch and Khalili, 2012

In the paper

“Taken together, multiple growth signaling nodes that become aberrantly activated in cancer share an ability to facilitate cellular access to glucose, a principal metabolic substrate.”

In the paper

“The carbon economy of a proliferating cell differs dramatically from that of a cell that is quiescent”

What the sources say

• Not checked yetcites Vander Heiden et al., 2009 source

In the paper

“cancer cells in vivo often encounter conditions of nutrient scarcity as a result of the increased rates of nutrient consumption and the inadequacies of the tumor vascular supply”

What the sources say

• Not checked yetcites Vaupel et al., 1989

In the paper

“The deletion of Rb family proteins has been shown to upregulate the uptake and utilization of glutamine via the E2F-dependent upregulation of ASCT2 and GLS1”

What the sources say

• Not checked yetcites Reynolds et al., 2014 source

In the paper

“An elevated expression of lipoprotein lipase (LPL) and monoacylglycerol lipase (MAGL) across diverse cancer subtypes and correlates with invasiveness”

What the sources say

• Not checked yetcites Kuemmerle et al., 2011 source
• Not checked yetcites Nomura et al., 2010 source

In the paper

“supplementation of culture medium with physiological levels (20–30 mg/mL) of serum albumin enables proliferation of KRASG12D-transformed MEFs in the absence of an essential amino acid leucine”

What the sources say

• Not checked yetcites Palm et al., 2015 source

In the paper

“Taken together, tumor cells utilize opportunistic modes of nutrient acquisition, which allow them to survive and proliferate in metabolically unfavorable conditions.”

In the paper

“genetic alterations that target PI-3 kinase, its negative regulators PTEN and INPP4B, as well as activating mutations and gene amplifications in a variety of upstream receptor tyrosine kinases, result in constitutive glucose uptake and metabolism in diverse cancer types.”

In the paper

“The transcription factor c-myc, which is upregulated in proliferating cells and is frequently targeted by amplification in various tumor types, is a principal driver of glutamine utilization by proliferating cells”

What the sources say

• Not checked yetcites Wang et al., 2011b
• Not checked yetcites Wise et al., 2008 source

In the paper

“However, autophagy cannot supply cells with new biomass and thus cannot support proliferation in nutrient-poor conditions.”

In the paper

“PI3K/Akt signaling acts as a master regulator of glucose uptake.”

In the paper

“glutamine uptake is also subject to negative regulation by the Rb tumor suppressor family of proteins.”

In the paper

“cancer cells can withstand long periods of nutrient deprivation via the self-catabolic process of macroautophagy”

What the sources say

• Not checked yetcites Boya et al., 2013 source

In the paper

“capture of extracellular macromolecules occurs through macropinocytosis, a process in which bulk extracellular fluid is taken up into giant vesicles”

What the sources say

• Not checked yetcites Kerr and Teasdale, 2009

In the paper

“hypoxia compromises stearoyl-CoA desaturase 1 (SCD1)-catalyzed introduction of double bonds into the de novo produced fatty acids, creating a deficit of unsaturated fatty acid species.”

In the paper

“cells that harbor a mutant KRAS allele are more likely to perpetrate entosis than to be consumed in this process”

What the sources say

• Not checked yetcites Sun et al., 2014 source

In the paper

“autophagy allows nutrient- or growth factor-deprived cells to maintain their viability in culture for weeks”

What the sources say

• Not checked yetcites Lum et al., 2005 source

In the paper

“hypoxic cells import “ready-made” unsaturated fatty acids from the surrounding environment in a form of single acyl chain-containing lysophospholipids”

What the sources say

• Not checked yetcites Kamphorst et al., 2013 source

In the paper

“its γ-carbon can be transferred to a carrier molecule, tetrahydrofolate (THF), in a reaction catalyzed by serine hydroxylmethyltransferase 2 (SHMT2) in the mitochondria, and SHMT1 in the cytosol, generating 5, 10-methylene-THF and glycine.”

In the paper

“Such apparent dichotomy in utilization of carbon for either predominantly biosynthetic or predominantly bioenergetic purposes may explain why tumors retain the capacity for oxidative phosphorylation, despite the original hypothesis put forth by Otto Warburg.”

In the paper

“Even with these adaptations, proliferating cells often accumulate electron transport flux that exceeds the capacity of the ATP synthase, resulting in the formation of excess reactive oxygen species (ROS).”

In the paper

“Triggered by the introduction of a mutant BRAF or RAS alleles, OIS is associated with a profound oxidative damage and irreversible growth arrest (Courtois-Cox et al., 2008).”

What the sources say

• Not checked yetcites Courtois-Cox et al., 2008 source

In the paper

“the use of 3-phosphoglycerate as a precursor for the biosynthesis of serine, glycine, and as a means to generate methyl donor groups and NADPH.”

In the paper

“Serine has a unique metabolic role in the cell as a major substrate for the so-called one-carbon, or folate cycle.”

In the paper

“The emerging evidence favors the hypothesis that glycolysis is utilized by proliferating cells as a versatile production line that generates metabolic intermediates for numerous biosynthetic processes.”

In the paper

“Utilization of PPP is frequently elevated in tumorigenesis.”

In the paper

“Unlike PKM1, PKM2’s activity is highly regulated.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Chaneton et al., 2012; Christofk et al., 2008b; Ye et al., 2012

In the paper

“To this end, Akt activates the ATP-citrate lyase (ACLY) enzyme, which catalyzes cytosol-localized cleavage of the TCA cycle-derived citrate into acetyl-CoA and oxaloacetate (Bauer et al., 2005; Berwick et al., 2002).”

What the sources say

• Not checked yetcites Bauer et al., 2005 source
• Not checked yetcites Berwick et al., 2002 source

In the paper

“stepwise oxidation of one-carbon-THF species was recently shown to produce up to 50% of all cellular NADPH”

What the sources say

• Not checked yetcites Fan et al., 2014 source

In the paper

“For instance, c-myc coordinately increases the expression of PDK1, lactate dehydrogenase A (LDH-A), an enzyme which catalyzes the reductive conversion of pyruvate to lactate, and monocarboxylate transporter (MCT1), which facilitates the efflux of lactate into the extracellular space (Wahlstrom and Arsenian Henriksson, 2015).”

What the sources say

• Not checked yetcites Wahlstrom and Arsenian Henriksson, 2015

In the paper

“To balance biosynthetic outputs of glycolysis with its role in providing pyruvate that supports TCA cycle activity, proliferating cells have evolved a novel mechanism by which to regulate the last step of glycolysis.”

In the paper

“suggesting that alterations in the one-carbon pathway may be universally selected for in tumorigenesis”

In the paper

“In fact, the damaging consequences of the overproduction of ROS from the overloaded electron transport chain may underlie the phenomenon of oncogene-induced cellular senescence (OIS).”

In the paper

“Fructose-6-phosphate, which follows glucose-6-phosphate in the glycolytic pathway, can also leave glycolysis and become utilized as a substrate for hexosamine biosynthesis.”

In the paper

“In such a manner, growth factor-dependent signal transduction inhibits PKM2, leading to accumulation of glycolytic intermediates until the growing cell’s need for a catabolizable pool of free serine is saturated.”

In the paper

“Finally, stabilization of HIF1α by hypoxia or in various oncogenic contexts also triggers coordinated transcriptional upregulation of LDH-A and PDK1 (Kim et al., 2006; Papandreou et al., 2006).”

What the sources say

• Not checked yetcites Kim et al., 2006 source
• Not checked yetcites Papandreou et al., 2006 source

In the paper

“Interestingly, attenuation of the activity of pyruvate dehydrogenase (PDH), a gatekeeper enzyme that converts pyruvate into acetyl-CoA, via the ectopic expression of its negative regulator pyruvate dehydrogenase kinase 1 (PDK1) or an RNAi-mediated depletion of a PDH phosphatase PDP2 was found to bypass mutant BRAFV600E-induced OIS and potentiate tumorigenesis (Kaplon et al., 2013).”

What the sources say

• Not checked yetcites Kaplon et al., 2013 source

In the paper

“Oxaloacetate is converted to malate and re-imported into mitochondria to maintain anaplerosis”

In the paper

“In addition to c-myc, TCF/β-catenin signaling has also been shown to upregulate MCT1 and PDK1 transcription (Pate et al., 2014).”

What the sources say

• Not checked yetcites Pate et al., 2014 source

In the paper

“In addition to serine, PKM2 can also be allosterically activated by excess accumulation of other byproducts of glucose metabolism including succinylaminoimidazolecarboxamide (SAICAR), an intermediate product of ribose-5-phosphate biosynthesis (Keller et al., 2012).”

What the sources say

• Not checked yetcites Keller et al., 2012 source

In the paper

“In fact, increased activity of GPDH has been detected in prostate cancer cells, insulinomas and carcinoid tumors (Chowdhury et al., 2005; MacDonald et al., 1990).”

What the sources say

• Not checked yetcites Chowdhury et al., 2005 source
• Not checked yetcites MacDonald et al., 1990

In the paper

“methylene tetrahydrofolate dehydrogenase 2 (MTHFD2), a component of the mitochondrial arm of the one-carbon pathway, was found to be among the top three most frequently overexpressed metabolic enzymes in cancer”

What the sources say

• Not checked yetcites Nilsson et al., 2014 source

In the paper

“A variety of oncogenes have been shown to contribute to the metabolic adaptations of proliferating cells outlined above.”

In the paper

“In addition to glycolytic intermediates, growth factor signaling promotes the use of select TCA cycle intermediates in the generation of biosynthetic precursors as well.”

In the paper

“One-carbon-THF species are utilized as substrates for the biosynthesis of purines, thymidine, as well as in the production of S-adenosylmethionine, a principal substrate for cellular methylation reactions.”

In the paper

“hypoxia-driven induction of SHMT2 expression was shown to protect cells from hypoxia-associated oxidative stress”

What the sources say

• Not checked yetcites Ye et al., 2014

In the paper

“Excess NADH generated by glycolysis is not imported into mitochondria of proliferating cells solely through chemical shuttles but is also utilized to convert the glycolytic intermediate DHAP into glycerol-3-phosphate that donates electrons directly into the electron transport chain utilizing glycerol-3-phosphate dehydrogenase (mGPDH) localized to the outer mitochondrial membrane.”

In the paper

“cancer cells may utilize as much as 50% of glucose-derived carbon in serine biosynthesis and its subsequent catabolism”

What the sources say

• Not checked yetcites Locasale et al., 2011 source

In the paper

“Whereas overproduction of ROS is detrimental to cell growth and survival, moderate levels of ROS, which are generated either during respiration or in a targeted manner by a class of NADPH oxidases, constitute an important signaling input that contributes to the maintenance of the tumorigenic state (Sullivan and Chandel, 2014).”

What the sources say

• Not checked yetcites Sullivan and Chandel, 2014

In the paper

“Mitochondria are protected further from excess glycolysis because any pyruvate that does enter the TCA cycle is channeled into citrate that is secreted into the cytosol through the mitochondrial tricarboxylate carrier and broken down into acetyl-CoA and oxaloacetate.”

In the paper

“In particular, PI3K/Akt activation allows a cell to expand its cytosolic pool of acetyl-CoA, a substrate for the de novo biosynthesis of fatty acids.”

What the sources say

• Not checked yetcites Bauer et al., 2005 source
• Not checked yetcites Berwick et al., 2002 source

In the paper

“The electrons entering the mitochondrial electron transport chain through glycerol phosphate dehydrogenase activity and Complex I as a result of mitochondrial conversion of malate to oxaloacetate are sufficient to maintain both mitochondrial integrity and ATP production despite reduced catabolic TCA cycle activity.”

In the paper

“In contrast, biosynthesis of asparagine from aspartate, catalyzed by asparagine synthetase (ASNS), utilizes the amide nitrogen of glutamine.”

In the paper

“Glutamine synthetase (GS) has been found to be overexpressed in some cancers (Osada et al., 2000);”

What the sources say

• Not checked yetcites Osada et al., 2000 source

In the paper

“In addition, the assembly of both pyrimidine and purine rings utilizes aspartate, which is derived from the transamination of the TCA cycle metabolite oxaloacetate and glutamic acid, both of which are catabolites of glutamine.”

In the paper

“Besides the regulatory inputs from c-myc, mutant p53 alleles have also been shown to facilitate expression of nucleotide biosynthesis genes, among which are IMPDH1 and 2, GMP synthetase (GMPS) and nucleoside salvage enzymes deoxycytidine kinase (DCK) and thymidine kinase (TK1) (Kollareddy et al., 2015).”

What the sources say

• Not checked yetcites Kollareddy et al., 2015 source

In the paper

“To maintain the ability to synthesize these amino acids, their production must be carefully balanced with an anaplerotic influx into the cycle.”

In the paper

“Yet despite this, asparagine plays a crucial regulatory role in conditions of glutamine deprivation (Zhang et al., 2014).”

What the sources say

• Not checked yetcites Zhang et al., 2014 source

In the paper

“Indeed, a proliferating cell must synthesize a number of nitrogen-containing molecules de novo, including nucleotides, non-essential amino acids and polyamines.”

In the paper

“Among the c-myc-regulated targets are phosphoribosyl pyrophosphate synthetase 2 (PRPS2), which catalyzes a first step of purine biosynthesis, as well as carbamoyl phosphate synthetase II (CAD), which initiates the pyrimidine ring-building cascade (Cunningham et al., 2014; Eberhardy and Farnham, 2001; Mannava et al., 2008).”

What the sources say

• Not checked yetcites Cunningham et al., 2014 source
• Not checked yetcites Eberhardy and Farnham, 2001
• Not checked yetcites Mannava et al., 2008 source

In the paper

“Anaplerotic entry of glucose-derived carbons into the TCA cycle takes place via carboxylation of pyruvate into the TCA cycle intermediate oxaloacetate, catalyzed by pyruvate carboxylase (PC).”

In the paper

“The oncogene c-myc orchestrates nucleotide biosynthesis by upregulating the expression of a number of nucleotide biosynthesis enzymes.”

In the paper

“furthermore, a similar accumulation of glucose-derived glutamine within the tumor tissue was observed in a mouse model of c-Met-driven liver cancer (Yuneva et al., 2012).”

What the sources say

• Not checked yetcites Yuneva et al., 2012 source

In the paper

“Arginine, despite being a non-essential amino acid, also becomes conditionally essential in some tumorigenic contexts (Figure 5).”

In the paper

“Oxidation of glutamine-derived α-ketoglutarate into oxaloacetate not only helps to maintain the ability of cells to synthesize citrate.”

In the paper

“In contrast, acute lymphoblastic leukemia cells lack ASNS expression, leading to asparagine auxotrophy.”

In the paper

“As discussed above, the transcriptional effects of c-myc and E2F result in enhanced cellular uptake of glutamine.”

In the paper

“Though structurally similar to glutamine, asparagine is the only amino acid that mammalian cells do not catabolize.”

In the paper

“In fact, tracing the fate of glucose-derived carbons in human patients and in mouse models of glioblastoma and non-small cell lung carcinoma (NSCLC) reveals that at least in these tumorigenic contexts, the principal source for the TCA cycle intermediates is not glutamine, but glucose (Maher et al., 2012; Marin-Valencia et al., 2012; Sellers et al., 2015).”

What the sources say

• Not checked yetcites Maher et al., 2012 source
• Not checked yetcites Marin-Valencia et al., 2012 source
• Not checked yetcites Sellers et al., 2015 source

In the paper

“The major anaplerotic substrate in growing cells is glutamine.”

In the paper

“Accordingly, glutamine levels have been shown to be rate-limiting for cell cycle progression, and glutamine deprivation leads to cell cycle arrest in the S-phase in certain cellular contexts (Fontenelle and Henderson, 1969; Gaglio et al., 2009).”

What the sources say

• Not checked yetcites Fontenelle and Henderson, 1969
• Not checked yetcites Gaglio et al., 2009 source

In the paper

“Despite the existence of a glutamine biosynthetic pathway in mammalian cells, the majority of proliferating cells in culture require an exogenous supply of glutamine.”

In the paper

“Specifically, a variety of tumor types localized to the brain, including primary glioblastomas as well as brain metastases that originated from other tissues, have been shown to assimilate exogenous acetate and incorporate acetate-derived carbons into de novo synthesized fatty acids (Comerford et al., 2014; Mashimo et al., 2014; Schug et al., 2015).”

What the sources say

• Not checked yetcites Comerford et al., 2014 source
• Not checked yetcites Mashimo et al., 2014 source
• Not checked yetcites Schug et al., 2015 source

In the paper

“Accordingly, glutamine levels have been shown to be rate-limiting for cell cycle progression, and glutamine deprivation leads to cell cycle arrest in the S-phase in certain cellular contexts (Fontenelle and Henderson, 1969; Gaglio et al., 2009).”

What the sources say

• Not checked yetcites Fontenelle and Henderson, 1969
• Not checked yetcites Gaglio et al., 2009 source

In the paper

“The amide group of glutamine is an indispensable donor of nitrogen for the biosynthesis of purine and pyrimidine bases (Figure 5).”

In the paper

“Interestingly, some cell types, such as embryonic stem cells and luminal breast cancer cells, are capable of proliferating in the absence of glutamine in the culture medium, indicating that in some cellular contexts, glutamine can be produced de novo (Carey et al., 2015; Kung et al., 2011).”

What the sources say

• Not checked yetcites Carey et al., 2015 source
• Not checked yetcites Kung et al., 2011 source

In the paper

“In addition to fatty acid production, the de novo biosynthesis of cholesterol from malonyl-CoA plays a role in tumorigenesis as well.”

What the sources say

• Not checked yetcites Freed-Pastor et al., 2012 source

In the paper

“In fact, aspartate biosynthesis has recently been shown to be critically dependent upon a cell’s ability to conduct oxidative phosphorylation (Birsoy et al., 2015; Sullivan et al., 2015).”

What the sources say

• Not checked yetcites Birsoy et al., 2015 source
• Not checked yetcites Sullivan et al., 2015 source

In the paper

“Furthermore, upregulation of ACSS2 may potentially allow cells to recycle acetate released from deacetylation of histones and other cellular proteins as well.”

In the paper

“Finally, extracellular acetate has recently been shown to be utilized by some cancers as a source of acetyl-CoA for biosynthesis.”

What the sources say

• Not checked yetcites Comerford et al., 2014 source
• Not checked yetcites Mashimo et al., 2014 source
• Not checked yetcites Schug et al., 2015 source

In the paper

“In addition to supplying citrate, the TCA cycle also provides metabolic precursors for the biosynthesis of non-essential amino acids including aspartate and asparagine.”

In the paper

“Depletion of plasma asparagine by a recombinant form of bacterial L-Asparaginase is an effective anticancer intervention for this cancer type (Hill et al., 1967; Pieters et al., 2011).”

What the sources say

• Not checked yetcites Hill et al., 1967 source
• Not checked yetcites Pieters et al., 2011 source

In the paper

“Finally, α-ketoglutarate may provide a source of citrate for the de novo lipogenesis in a setting in which hypoxia or certain oncogenic contexts create a deficit of glucose-derived acetyl-CoA.”

In the paper

“Glutamine-derived glutamate serves as a donor of nitrogen for the production of a number of non-essential amino acids via transamination.”

In the paper

“Other targets of c-myc that are involved in nucleotide biosynthesis are thymidylate synthase (TS) and inosine monophosphate dehydrogenase 1 (IMPDH1) and 2 (IMPDH2) (Liu et al., 2008; Mannava et al., 2008).”

What the sources say

• Not checked yetcites Liu et al., 2008 source
• Not checked yetcites Mannava et al., 2008 source

In the paper

“In addition to increasing the consumption of carbon in biosynthetic pathways, growth signaling concomitantly elevates the cellular demand for reduced nitrogen.”

In the paper

“Most proliferating cells depend on a continuous supply of glutamine to maintain the integrity of TCA cycle intermediates (DeBerardinis et al., 2007).”

What the sources say

• Not checked yetcites DeBerardinis et al., 2007 source

In the paper

“In addition, human glioblastoma samples implanted directly into the brains of immunocompromised mice were found to accumulate glutamine relative to the normal brain tissue (Marin-Valencia et al., 2012);”

What the sources say

• Not checked yetcites Marin-Valencia et al., 2012 source

In the paper

“Thus, glutamine is a key structural building block in the biosynthesis of nucleotides.”

In the paper

“A number of recent reports demonstrate that histone and DNA methylation is sensitive to alterations in SAM levels (Chiang et al., 2009; Shyh-Chang et al., 2013; Towbin et al., 2012).”

What the sources say

• Not checked yetcites Chiang et al., 2009 source
• Not checked yetcites Shyh-Chang et al., 2013 source
• Not checked yetcites Towbin et al., 2012 source

In the paper

“In addition to acetyl-CoA, a p300 histone acetyltransferase has recently been shown to utilize crotonyl-CoA as a substrate as well.”

What the sources say

• Not checked yetcites Sabari et al., 2015 source

In the paper

“In fact, a meta-analysis of metabolic enzyme expression across diverse tumor types identified PYCR1 as one of the most commonly overexpressed genes in tumors (Nilsson et al., 2014).”

What the sources say

• Not checked yetcites Nilsson et al., 2014 source

In the paper

“Owing to its structural similarity to α-ketoglutarate, 2-HG acts as a competitive inhibitor of α-ketoglutarate-dependent dioxygenases (Xu et al., 2011).”

What the sources say

• Not checked yetcites Xu et al., 2011

In the paper

“Reduced expression of ASS1 and ASL are associated with poor prognosis and resistance to chemotherapy (McAlpine et al., 2014; Nicholson et al., 2009).”

What the sources say

• Not checked yetcites McAlpine et al., 2014 source
• Not checked yetcites Nicholson et al., 2009 source

In the paper

“IDH1 and IDH2 mutations have been identified in low-grade glioma, where they represent a likely initiator lesion, as well as in chondrosarcoma, cholangiocarcinoma, and acute myeloid leukemia (AML) (Balss et al., 2008; Borger et al., 2012; Cohen et al., 2013; Mardis et al., 2009; Parsons et al., 2008; Paschka et al., 2010).”

What the sources say

• Not checked yetcites Balss et al., 2008 source
• Not checked yetcites Borger et al., 2012 source
• Not checked yetcites Cohen et al., 2013 source

In the paper

“Activated Akt expands the extramitochondrial pool of acetyl-CoA by activating ACLY, which converts cytosolic citrate into acetyl-CoA and oxaloacetate.”

In the paper

“A key metabolite that builds up when cells metabolize more glucose than needed for bioenergetic support is cytosolic acetyl-CoA.”

In the paper

“In addition, α-ketoglutarate-dependent dioxygenases are prone to the inhibition by their reaction product, succinate, as well as by fumarate, the downstream product of succinate degradation in the TCA cycle.”

In the paper

“Furthermore, studies have shown that both the glucose- and oncogene-driven increases in global histone acetylation are blocked by ACLY inhibition (Lee et al., 2014; Wellen et al., 2009).”

What the sources say

• Not checked yetcites Lee et al., 2014 source
• Not checked yetcites Wellen et al., 2009 source

In the paper

“Notably, deposition of crotonyl marks on select amino acid residues within histone tails was found to activate gene expression even more potently than acetyl marks (Sabari et al., 2015).”

What the sources say

• Not checked yetcites Sabari et al., 2015 source

In the paper

“In contrast to wild-type isocitrate dehydrogenases, which convert the TCA cycle metabolite isocitrate to α-ketoglutarate, a mutant form of IDH prefers to use α-ketoglutarate as a substrate, catalyzing its conversion to the D-enantiomer of 2-hydroxyglutarate (2-HG) (Dang et al., 2010; Ward et al., 2010).”

What the sources say

• Not checked yetcites Dang et al., 2010 source
• Not checked yetcites Ward et al., 2010 source

In the paper

“Another possible reason for arginine auxotrophy in cancer may be related to the fact that the suppression of ASS1-driven argininosuccinate production leads to an accumulation of its substrate aspartate, which can then be applied toward nucleotide biosynthesis.”

In the paper

“A wide variety of post-translational modifications in the cell are carried out by the members of a large class of α-ketoglutarate-dependent dioxygenases.”

In the paper

“Cytosolic acetyl-CoA is the obligate substrate for enzymes that acetylate histones and other proteins.”

In the paper

“Crotonyl-CoA can be produced from the catabolism of lysine and tryptophan, as well as of a short-chain fatty acid butyrate.”

In the paper

“However, metabolic networks themselves are not merely passive recipients of growth signals, but quite the contrary, directly transmit the information about the cellular metabolic state to a diverse array of regulatory enzymes, among which are those that mediate the deposition and removal of epigenetic marks from chromatin (Katada et al., 2012)(Figure 6).”

What the sources say

• Not checked yetcites Katada et al., 2012 source

In the paper

“Another prominent class of tumor-associated genetic alterations that modulate the activity of α-ketoglutarate-dependent dioxygenases are gain-of-function mutations of isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2).”

In the paper

“Indeed, IDH-driven gliomas, leukemias and chondrosarcomas display a prominent CpG island hypermethylation, reminiscent of the hypermethylator phenotype seen in SDH- and FH-deficient cancers (Figueroa et al., 2010; Lu et al., 2013; Turcan et al., 2012).”

What the sources say

• Not checked yetcites Figueroa et al., 2010 source
• Not checked yetcites Lu et al., 2013
• Not checked yetcites Turcan et al., 2012 source

In the paper

“Taken together, while this area of cancer metabolism remains under active investigation, it is clear that similarly to carbon, the metabolism of nitrogen undergoes complex reprogramming in tumorigenesis.”

In the paper

“Numerous methylation reactions in the cell, including the deposition of methyl marks on histone tails, cytosine methylation on DNA and adenosine methylation on mRNA utilize S-adenosylmethionine (SAM) as a donor of methyl groups.”

In the paper

“Expression of POX has been shown to inhibit tumor cell growth by triggering cell cycle arrest in the G2 phase (Liu et al., 2009).”

What the sources say

• Not checked yetcites Liu et al., 2009 source

In the paper

“Sensitive to changes in NAD+ or FAD availability, these enzymes orchestrate global post-translational and epigenetic changes that promote energy conservation (Hino et al., 2012; Schwer and Verdin, 2008).”

What the sources say

• Not checked yetcites Hino et al., 2012 source
• Not checked yetcites Schwer and Verdin, 2008

In the paper

“The expression of the principal enzyme in proline biosynthesis, pyrroline-5-carboxylate reductase (PYCR1), is upregulated by c-myc (Liu et al., 2012).”

What the sources say

• Not checked yetcites Liu et al., 2012 source

In the paper

“The reaction mechanism of α-ketoglutarate-dependent dioxygenases involves a concurrent oxidation of a co-substrate α-ketoglutarate into succinate.”

In the paper

“Accordingly, the auxotrophy of tumors for arginine is being exploited in the development of anticancer therapies (Delage et al., 2010).”

What the sources say

• Not checked yetcites Delage et al., 2010 source

In the paper

“In addition to its effects on glutamine metabolism, c-myc-orchestrated remodeling of non-essential amino acid metabolism involves the metabolism of proline (Phang et al., 2008).”

What the sources say

• Not checked yetcites Phang et al., 2008 source

In the paper

“Histone acetylation is exquisitely sensitive to alterations in the cellular nutritional and signaling status (Cai et al., 2011; Shi and Tu, 2013).”

What the sources say

• Not checked yetcites Cai et al., 2011 source
• Not checked yetcites Shi and Tu, 2013 source

In the paper

“Immunohistochemical analysis of glioblastoma and prostate tumor samples has shown that Akt activation levels closely correlate with global histone acetylation status (Lee et al., 2014).”

What the sources say

• Not checked yetcites Lee et al., 2014 source

In the paper

“For instance, a biallelic loss of succinate dehydrogenase (SDH), an alteration found in familial paragangliomas and pheochromocytomas, as well as in a subset of sporadic gastrointestinal stromal tumors, creates a build-up of succinate (Astuti et al., 2001; Janeway et al., 2011).”

What the sources say

• Not checked yetcites Astuti et al., 2001 source
• Not checked yetcites Janeway et al., 2011 source

In the paper

“In fact, a large variety of novel histone marks, such as formylation, propionylation, butyrylation, malonylation and succinylation have recently been identified by tandem mass spectrometry (Chen et al., 2007; Wisniewski et al., 2008; Xie et al., 2012).”

What the sources say

• Not checked yetcites Chen et al., 2007 source
• Not checked yetcites Wisniewski et al., 2008 source
• Not checked yetcites Xie et al., 2012 source

In the paper

“Aberrantly activated growth and survival signals that drive tumorigenesis facilitate the reprogramming of cancer cell metabolism to enable increased nutrient acquisition and biosynthesis.”

In the paper

“Accordingly, intracellular levels of α-ketoglutarate can directly influence the activity of these enzymes.”

In the paper

“Intriguingly, both ASS1 and ASL enzymes are frequently epigenetically silenced in melanoma, renal cell carcinoma and hepatocellular carcinoma (Bowles et al., 2008; Ensor et al., 2002; Yoon et al., 2007).”

What the sources say

• Not checked yetcites Bowles et al., 2008 source
• Not checked yetcites Ensor et al., 2002
• Not checked yetcites Yoon et al., 2007 source

In the paper

“The removal of acetyl and methyl marks is also guided by the cellular metabolic state.”

In the paper

“In fact, the latter, at least in the context of SDH loss, can be reversed by the addition of a membrane-permeable form of α-ketoglutarate (MacKenzie et al., 2007).”

What the sources say

• Not checked yetcites MacKenzie et al., 2007 source

In the paper

“High dietary intake of choline has been linked to a significantly increased risk of lethal prostate cancer (Richman et al., 2012).”

What the sources say

• Not checked yetcites Richman et al., 2012 source

In the paper

“The secretion of lactate into the extracellular space via the monocarboxylate transporter MCT1 is coupled to the co-transport of H+, which causes acidification of the cellular microenvironment.”

In the paper

“Conversely, small molecule-mediated inhibition of mutant IDH1 in glioma and IDH2 in leukemia markedly promoted differentiation in these contexts (Rohle et al., 2013; Wang et al., 2013).”

What the sources say

• Not checked yetcites Rohle et al., 2013 source
• Not checked yetcites Wang et al., 2013 source

In the paper

“Consistent with its heavy utilization by cancer cells, cysteine was found to be the second most depleted amino acid in pancreatic tumors in comparison to normal pancreatic tissue (Kamphorst et al., 2015).”

What the sources say

• Not checked yetcites Kamphorst et al., 2015 source

In the paper

“In fact, no less than 30% of imported glutamine was shown to leave the cell through the xCT transporter as glutamate, while being exchanged for cysteine (Collins et al., 1998).”

What the sources say

• Not checked yetcites Collins et al., 1998 source

In the paper

“Expression of carbonic anhydrases, in particular the CAIX isoform, is elevated during hypoxia (Svastova et al., 2004).”

What the sources say

• Not checked yetcites Svastova et al., 2004 source

In the paper

“Reciprocally, the conditions within the tumor microenvironment have profound effects on the metabolism of a cancer cell.”

In the paper

“Furthermore, L-2-HG levels were found to increase in response to hypoxia as a result of promiscuous substrate use by LDH-A and malate dehydrogenase (MDH) (Intlekofer et al., 2015), and two recent studies implicate L-2-HG as a metabolic mediator of the cellular stress response to hypoxia (Intlekofer et al., 2015; Oldham et al., 2015).”

What the sources say

• Not checked yetcites Intlekofer et al., 2015 source
• Not checked yetcites Oldham et al., 2015 source

In the paper

“In addition, the surplus of CO2 generated in mitochondrial decarboxylation reactions contributes to the extracellular acidification as well. To this end, CO2 diffuses into the extracellular space, where it becomes converted to H+ and HCO3− by a class of extracellular carbonic anhydrases (Swietach et al., 2007).”

What the sources say

• Not checked yetcites Swietach et al., 2007 source

In the paper

“The high utilization of extracellular glucose and glutamine by cancer cells results in the accumulation of extracellular lactate, which was shown to affect a number of cell types within the tumor microenvironment.”

In the paper

“The abundance of 2-HG has been utilized for 1H magnetic resonance spectroscopy-based imaging of IDH-mutant gliomas (Choi et al., 2012).”

What the sources say

• Not checked yetcites Choi et al., 2012 source

In the paper

“In contrast, a diet high in choline and betaine was associated with a decreased breast and lung cancer risk (Xu et al., 2009a; Ying et al., 2013; Zhang et al., 2013).”

What the sources say

• Not checked yetcites Xu et al., 2009a
• Not checked yetcites Ying et al., 2013 source
• Not checked yetcites Zhang et al., 2013 source

In the paper

“In addition to these inputs, proliferating cancer cells alter the metabolic composition of the extracellular milieu around them as well (Figure 7).”

In the paper

“Two other dietary compounds that can be utilized as donors of methyl groups for SAM production are choline and its derivative betaine.”

In the paper

“Moreover, small molecule inhibitors of IDH1 and IDH2 have been reported to induce remissions in phase I clinical trials for treatment of AML patients with the respective mutations.”

In the paper

“For instance, multiple lines of evidence indicate that the metabolism of sulfur may undergo reprogramming in cancer.”

In the paper

“Furthermore, accumulated kynurenine acts as a ligand for aryl hydrocarbon receptor (AhR) (Opitz et al., 2011).”

What the sources say

• Not checked yetcites Opitz et al., 2011 source

In the paper

“Furthermore, lactate accumulation is instrumental for the promotion of angiogenesis.”

What the sources say

• Not checked yetcites Constant et al., 2000 source
• Not checked yetcites Schmid et al., 2007 source
• Not checked yetcites Sonveaux et al., 2012 source