Cancer Cell Metabolism: Warburg and Beyond

“…well-characterized downstream effector of insulin signaling, reprises its role in glucose uptake and utilization in the cancer setting (reviewed in Manning and Cantley, 2007), whereas the Myc transcription factor upregulates the expression of various metabolic genes (reviewed in Gordan et al.,…”

“Blood vessels recruited to the tumor microenvironment, however, are disorganized, may not deliver blood effectively, and therefore do not completely alleviate hypoxia (reviewed in Gatenby and Gillies, 2004).”

“HIF initiates a transcriptional program that provides multiple solutions to hypoxic stress (reviewed in Kaelin and Ratcliffe, 2008).”

“Fatty acid synthase, expressed at low levels in normal tissues, is upregulated in cancer and may also be required for tumorigenesis (reviewed in Menendez and Lupu, 2007).”

“Recent work has found that the cancer-specific M2-PK causes an increase in the incorporation of glucose carbons into lipids and, expanding the connection between growth factor sig- naling and cancer metabolism, may be regulated by phosphotyrosine binding (Christofk et al., 2008a, 2008b).”

“It is well established that AMP-kinase senses the AMP/ATP ratio (reviewed in Hardie, 2007), whereas mTOR (the mammalian target of rapamycin) senses cellular amino acid concentrations (Kim et al., 2008; Sancak et al., 2008).”

“Recently, it has been demonstrated that glutamine may be metabolized by the citric acid cycle in cancer cells and converted into lactate, producing NADPH for lipid biosynthesis and oxaloacetate for replenishment of Krebs cycle intermediates (DeBerardinis et al., 2007).”

“It is well established that AMP-kinase senses the AMP/ATP ratio (reviewed in Hardie, 2007), whereas mTOR (the mammalian target of rapamycin) senses cellular amino acid concentrations (Kim et al., 2008; Sancak et al., 2008).”

“…has been proposed that loss of succinate dehydrogenase and fumarate hydratase causes an accumulation of succinate or fumarate, respectively, leading to inhibition of the prolyl hydroxylases that mark HIF for VHL-mediated degradation (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”

“Loss of the p53 target TIGAR sensitizes cancer cells to apoptosis, most likely by causing an increase in reactive oxygen species (Bensaad et al., 2006).”

“…must either increase flux through normal ATP-generating processes, or else rely on an increased diversity of fuel sources (G). the gene encoding SCO2 (the synthesis of cytochrome c oxidase protein), which interferes with the function of the mitochondrial respiratory chain (Matoba et al., 2006).”

“As pyruvate must enter the mitochondria in this case, it avoids conversion to lactate and therefore cannot contribute to glycolysis-derived ATP.”

“Intriguingly, Bonnet et al. (2007) have reported that treating cancer cells with dichloroacetate (DCA), a small molecule inhibitor of pyruvate dehydrogenase kinase, has striking effects on their survival and on xenograft tumor growth.”

“It is well established that AMP-kinase senses the AMP/ATP ratio (reviewed in Hardie, 2007), whereas mTOR (the mammalian target of rapamycin) senses cellular amino acid concentrations (Kim et al., 2008; Sancak et al., 2008).”

“The signaling molecule Ras, a powerful oncogene when mutated, promotes glycolysis (reviewed in Dang and Semenza, 1999; Ramanathan et al., 2005).”

“It has been shown that inhibition of lactate dehydrogenase A (LDH-A) prevents the Warburg effect and forces cancer cells to revert to oxidative phosphorylation in order to reoxidize NADH and produce ATP (Fantin et al., 2006; Shim et al., 1997).”

“Inhibition of ATP citrate lyase, the distal enzyme that converts mitochondrial-derived citrate into cytosolic acetyl coenzyme A, the precursor for many lipid species, prevents cancer cell proliferation and tumor growth (Hatzivassiliou et al., 2005).”

“Androgen-independent prostate cancer cells still express the androgen receptor and may be capable of autonomously synthesizing their own androgens (Stanbrough et al., 2006).”

“Recent work has found that the cancer-specific M2-PK causes an increase in the incorporation of glucose carbons into lipids and, expanding the connection between growth factor sig- naling and cancer metabolism, may be regulated by phosphotyrosine binding (Christofk et al., 2008a, 2008b).”

“…has been proposed that loss of succinate dehydrogenase and fumarate hydratase causes an accumulation of succinate or fumarate, respectively, leading to inhibition of the prolyl hydroxylases that mark HIF for VHL-mediated degradation (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”

“…has been proposed that loss of succinate dehydrogenase and fumarate hydratase causes an accumulation of succinate or fumarate, respectively, leading to inhibition of the prolyl hydroxylases that mark HIF for VHL-mediated degradation (Isaacs et al., 2005; Pollard et al., 2005; Selak et al., 2005).”

“Indeed, acidosis often precedes angiogenesis, and lactate may stimulate HIF expression independently of hypoxia (Fukumura et al., 2001; Lu et al., 2002; Shi et al., 2001).”

“…downstream effector of insulin signaling, reprises its role in glucose uptake and utilization in the cancer setting (reviewed in Manning and Cantley, 2007), whereas the Myc transcription factor upregulates the expression of various metabolic genes (reviewed in Gordan et al., 2007).”

“Surprisingly, the M2-PK of cancer cells is thought to be less active in the conversion of PEP to pyruvate and thus less efficient at ATP production (reviewed in Mazurek et al., 2005).”

“Other work also suggests that p53-mediated regulation of glucose metabolism may be dependent on the transcription factor NF-κB (Kawauchi et al., 2008).”

“On the other hand, overexpression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) prevents caspase-independent cell death, presumably by stimulating glycolysis, increasing cellular ATP levels, and promoting autophagy (Colell et al., 2007).”

“The tumor-stroma interaction may therefore have a metabolic component (Koukourakis et al., 2006).”

“The signaling molecule Ras, a powerful oncogene when mutated, promotes glycolysis (reviewed in Dang and Semenza, 1999; Ramanathan et al., 2005).”

“Much of the evidence for lactate as a multifunc- Cell 134, September 5, 2008 ©2008 Elsevier Inc. 705 tional metabolite comes from work in exercise physiology and muscle metabolism (reviewed in Philp et al., 2005).”

“However, the introduction of similar defined factors into human mesenchymal stem cells (MSCs) revealed that transformation can be associated with increased dependence on oxidative phosphorylation (Funes et al., 2007).”

“Indeed, acidosis often precedes angiogenesis, and lactate may stimulate HIF expression independently of hypoxia (Fukumura et al., 2001; Lu et al., 2002; Shi et al., 2001).”

“Inhibition of these adaptive mechanisms can lead to decreased viability of cancer cells and increased sensitivity to chemotherapeutic agents (reviewed in Fais et al., 2007; Fang et al., 2006).”

“Transported by several monocarboxylate transporters, lactate may be shared and metabolized among cells, although the idea is still controversial (Hashimoto et al., 2006; Yoshida et al., 2007).”

“Although there are enzymes that detoxify exogenous toxins, several “house-cleaning” enzymes, a term coined from studies in bacteria, deal with endogenous toxic metabolites (reviewed in Galperin et al., 2006).”

“Inhibition of these adaptive mechanisms can lead to decreased viability of cancer cells and increased sensitivity to chemotherapeutic agents (reviewed in Fais et al., 2007; Fang et al., 2006).”

“Transported by several monocarboxylate transporters, lactate may be shared and metabolized among cells, although the idea is still controversial (Hashimoto et al., 2006; Yoshida et al., 2007).”

“Suppression of DUT sensitizes some can- cer cells to pyrimidine antimetabolites, suggesting that inhibition of these cellular house-cleaning enzymes may be an effective adjunct chemotherapeutic strategy (Koehler and Ladner, 2004).”

“They do so in part by upregulating glucose transporters, notably GLUT1, which substantially increases glucose import into the cytoplasm (Jones and Thompson, 2009; DeBerardinis et al., 2008; Hsu and Sabatini, 2008).”

“Akt promotes proliferation, survival and nutrient uptake in cancer cells (reviewed in Ref”