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nated by systemic administration of asparaginase. Ultimately, effective metabolic therapy will require defining the stage of tumor progression in which each pathway provides its benefit to the cancer cell. Some activities first become essential very early in tumorigenesis as the nascent tumor begins to experience nutrient limitations (6). In other cases, altered pathways may be dispensable in primary tumors but essential for metastasis (7, 8). Because new therapeutic targets are nominated from simple experimental models like cultured cells, it will be essential to define their context-specific roles in biologically accurate models of tumor initiation and progression.
contain mutations that allow the PI3K-AKT-mTOR network to achieve high levels of signaling with minimal dependence on extrinsic stimulation by growth factors (17). Many of the best-characterized oncogenes and tumor suppressors reside in the PI3K-AKT-mTOR network, and aberrant activation of this pathway is among the most frequent alterations seen in a diverse set of cancers. Another commonly deregulated pathway in cancer is gain of function of MYC by chromosomal translocations, gene amplification, and single-nucleotide polymorphisms. MYC increases the expression of many genes that support anabolic growth, including transporters and enzymes involved in glycolysis, fatty acid synthesis, glutaminolysis, serine metabolism, and mitochondrial metabolism (18). Oncogenes like Kras, which is frequently mutated in lung, colon, and pancreatic cancers, co-opt the physiological functions of PI3K and MYC pathways to promote tumorigenicity. Aside from oncogenes, tumor suppressors such as the p53 transcription factor can also regulate metabolism (19). The p53 protein–encoding gene TP53 (tumor protein p53) is mutated or deleted in 50% of all human cancers. The tumor-suppressive functions of p53 have been ascribed to execution of DNA repair, cell cycle arrest, senescence, and apoptosis. However, recent studies indicate that p53 tumor-suppressive actions might be independent of these canonical p53 activities but rather dependent on the regulation of metabolism and oxidative stress (20, 21). Loss of p53 increases glycolytic flux to promote anabolism and redox balance, two key processes that promote tumorigenesis (19).
by the inheritance of biallelic mutations in the gene encoding L2HGDH (45). Affected children have seizures, mental retardation, white matter abnormalities of the brain, and systemically elevated levels of L2HG. Remarkably, a number of these children have developed malignant brain tumors (46), providing an early clue to the significance of D2HG in IDH1/IDH2-mutant gliomas and raising the question of whether L2HG is also an oncometabolite. L2HG and D2HG exhibit different effects on dioxygenase function (38), suggesting that the sensitivity of a particular tissue to the presence of either metabolite may depend on which dioxygenases are expressed. Recent work has demonstrated modest accumulation of L2HG in cells experiencing hypoxia or electron transport chain (ETC) dysfunction (42, 47) and in human renal cell carcinomas, which frequently display epigenetic silencing of L2HGDH (48). It is unknown whether reducing L2HG levels in these settings will promote cellular differentiation or suppress tumor progression. The principle that oncometabolites exert their effects outside of the conventional metabolic network also applies to the other two molecules that can reasonably be called oncometabolites: fumarate and succinate (28). Both are TCA cycle intermediates found throughout the body, but some tumors accumulate massive levels of fumarate and/or succinate as a consequence of loss-of-function mutations in FH or the SDH complex, respectively (49–51). Although these mutations markedly reprogram metabolism by impairing TCA cycle flux, the extent to which fumarate and succinate participate in cancer development likely involves their nonmetabolic functions (28). Like D2HG, evidence indicates that succinate and fumarate interfere with dioxygenase activity, supporting the notion that a general property of oncometabolites is the ability to regulate epigenetics (52, 53). PHGDH overexpression and mutations in IDH1/ IDH2, SDH, and FH all alter metabolite levels that control epigenetics (54). Several other metabolites, including acetyl-CoA, a-ketoglutarate, and S-adenosylmethionine also participate in epigenetic reprogramming, and time will tell whether genetically specific alterations of these metabolites in tumors promote tumorigenesis (54). Some metabolites, notably fumarate, covalently bind to sulfhydryl groups in glutathione, proteins, and peptides, altering their function and perhaps accounting for another mechanism by which oncometabolites promote or perpetuate malignant phenotypes (55–58).
activates catabolic pathways like fatty acid oxidation to stimulate ATP production (84). In conditions of metabolic stress, certain Ras-driven cancer cells scavenge lipids to support ATP production (85). Ovarian cancer cells use fatty acids from neighboring adipocytes to fuel mitochondrial ATP production (86). Thus, there are multiple mechanisms by which cancer cells maintain their ATP/ADP ratio to sustain viability in nutrient- and oxygen-poor environments.
Fig. 2. Metabolic pathways under nutrient-replete and nutrient-deprived conditions. Accessibility to nutrients within solid tumors is regulated by proximity to the vasculature. Cells located adjacent to the vasculature use nutrients and oxygen to fuel anabolic pathways that support proliferation. However, cells distant from the vasculature have diminished accessibility to nutrients and oxygen and may engage in alternative forms of metabolism including oxidation of fatty acids and BCAAs as well as macromolecular degradation through autophagy and macropinocytosis to support cell viability.
points to a distinct mechanism by which activation of the signaling pathway enables nucleotide biosynthesis. The mTORC1 effector ribosomal S6K1 phosphorylates the trifunctional enzyme CAD (carbamoylphosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase), which catalyzes the first three steps of pyrimidine synthesis (113). Phosphorylation on CAD S1859 is required for mTORC1-dependent stimulation of pyrimidine biosynthesis (113). Additional work is needed to determine how other aspects of de novo nucleotide synthesis, purine and pyrimidine salvage pathways, and accessory activities like folate metabolism are regulated in cancer cells in support of cell proliferation.
REVIEW and NOX inhibitors can prevent cancer cell proliferation, hypoxic activation of HIF, tumorigenesis, and metastasis (64, 123–125). The increased localized ROS in cancer cells, which activates signaling pathways and transcription factors to promote tumorigenesis, needs to be buffered from reaching levels of ROS that incur cellular damage by the increased expression of antioxidant proteins (126). Thus, cancer cells have higher levels of ROS scavenging enzymes than normal cells, preventing ROS-mediated activation of death-inducing pathways like c-Jun N-terminal kinase (JNK) and p38 MAPK and oxidation of lipids, proteins, and DNA, resulting in irreversible damage and cell death. One mechanism by which cancer cells increase their antioxidant capacity is by activating the transcription factor nuclear factor (erythroidderived 2)–related factor-2 (NRF2) (127). Specifically, NRF2 is activated following disruption of the interaction of NRF2 with its binding partner Kelch-like ECH-associated protein 1 (KEAP1). Critical cysteine residues within KEAP1 can undergo oxidation, succination, and glutathionylation, thereby inhibiting the KEAP1-NRF2 interaction, leading to the proteasomal degradation of NRF2. Additionally, NRF2 activation can occur independently of KEAP1 (128). Once activated, NRF2 induces the transcription of many antioxidant proteins including GPXs and TXNs as well as enzymes involved in GSH synthesis and cysteine import through the cysteine/ glutamate antiporter. Furthermore, to maintain the antioxidant capacity of GPXs and TXNs, NADPH is required. NRF2 plays an important role in activating enzymes that increase cytosolic NADPH levels. NRF2 also regulates the serine biosynthesis pathway, generating NADPH in the mitochondria, which is critical for redox balance under hypoxic conditions (129, 130). Therefore, inactivating NRF2 or disabling antioxidant proteins in cancer cells would allow for the accumulation of excessive amounts of ROS to levels that initiate toxicity and reduce tumorigenesis (128, 131, 132). During tumorigenesis and metastasis, redox homeostasis is required (Fig. 4). An emerging model of redox balance is that as a tumor initiates, the metabolic activity of cancer cells is increased, resulting in an increase in ROS production and subsequent activation of signaling pathways that support cancer cell proliferation, survival, and metabolic adaptation (126). Accordingly, to prevent toxic levels of ROS, tumor cells increase their antioxidant capacity to allow for cancer progression (133). The harsh tumor microenvironment increases ROS levels due to hypoxia, and the low glucose levels limit flux through the cytosolic oxidative PPP, thus decreasing cytosolic NADPH levels. Cells in these nutrient-deprived conditions activate AMPK to increase NADPH levels by stimulating PPPdependent NADPH and diminishing anabolic pathways, such as lipid synthesis, that require high levels of NADPH (134, 135). ROS-dependent signaling and increased mitochondrial respiration are also necessary for tumor metastasis (124, 136). However, when tumor cells detach from a matrix, they encounter high levels of ROS that incur cellular damage and require activation of adaptive ROS-mitigating pathways to survive and grow (137, 138). The ability to up-regulate antioxidant proteins and increase flux through NADPH-producing metabolic pathways enables distant metastasis to occur (8). These findings suggest that perhaps disabling antioxidant capacity in cancer cells to raise ROS levels might be beneficial in preventing metastasis.
Fig. 4. Cancer cells maintain redox balance. Cancer cells have increased rates of ROS production due to activation of oncogenes and loss of tumor suppressors that promote signaling pathways supporting proliferation and survival. However, cancer cells prevent the buildup of ROS to levels that incur damage by increasing antioxidant capacity through induction of NRF2-dependent genes and, in glucose replete conditions, the use of PPP to generate NADPH. As cells encounter hypoxia and low glucose due to limited vasculature accessibility, the levels of ROS further increase, requiring AMPK and onecarbon metabolism to enhance NADPH production to raise antioxidant capacity. Loss of matrix attachment and escape of cancer cells into the blood for dissemination to distant sites incur further increases in ROS levels, which require additional enhancements of antioxidant defenses to avoid cell death. It is important to note that too little ROS or too high steady-state ROS levels within cancer cells result in failure for solid tumor progression and metastasis.
NADP+ to NADPH. However, certain tumors rely on this pathway as a major source of cytosolic NADPH; therefore, it may be therapeutic to disable this pathway and induce oxidative stress and diminish tumor growth. Moreover, RNA profiling of metabolic enzymes identified the mitochondrial one-carbon metabolism protein MTHFD2, which can generate NADPH, as being highly expressed in 19 different cancer types but not in normal adult proliferating cells (152). Loss of MTHFD2 in cancer cells increases ROS levels and sensitizes the cells to oxidant-induced cell death in vitro. An interesting approach to depleting NADPH levels and increasing ROS is to administer high doses of vitamin C (ascorbate). Vitamin C is imported into cells through sodium-dependent vitamin C transporters, whereas the oxidized form of vitamin C, dehydroascorbate (DHA), is imported into cells through glucose transporters such as GLUT1 (179). When the cell takes up DHA, it is reduced back to vitamin C by glutathione (GSH), which consequently becomes GSSG. Subsequently, GSSG is converted back to GSH by NADPH-dependent GR. Because the blood is an oxidizing environment, vitamin C becomes oxidized to DHA before being taken up by the cell. Thus, high doses of vitamin C diminish the tumorigenesis of colorectal tumors that harbor oncogenic KRAS mutations and express high levels of GLUT1 by depleting the NADPH and GSH pools and consequently increasing ROS levels to induce cancer cell death (179, 180). Vitamin C administered at high doses intravenously is safe in humans and, in conjunction with conventional paclitaxel-carboplatin therapy, demonstrated a benefit in a small number of patients (181). Additional strategies to diminish GSH include the administration of buthionine sulfoximine, an irreversible inhibitor of g-glutamylcysteine synthetase, which can be safely administered to humans and is efficacious in preclinical tumor models (182). Moreover, glutathione is a tripeptide consisting of cysteine, glutamate, and glycine. Thus, decreasing glutamate levels using glutaminase inhibitors or diminishing cysteine levels by preventing extracellular cysteine (two linked cysteine molecules) uptake can also raise ROS levels in cancer cells to induce cell death. An important consideration is that normal stem cells are sensitive to ROS levels; thus, it is important to stratify patients on the basis of their expression levels of a particular antioxidant protein or antioxidant pathway. It is critical to determine which antioxidant pathways are likely up-regulated as a result of the high rate of ROS production within cancer cells. Many cancer types use the NRF2 pathway to maintain redox balance; therefore, targeting this pathway may provide a viable therapeutic opportunity (128). Additionally, superoxide dismutase 1 (SOD1) is overexpressed in NSCLC, and its inhibition kills human NSCLC cells and decreases the tumor burden in mouse models of NSCLC (183). Because NRF2 and SOD1 knockout mice develop normally, short-term inhibition of these pathways might be an effective way to kill cancer cells.
REVIEW metabolomics and metabolic flux analysis, has uncovered novel functions and liabilities of this pathway in cancer cell growth and stress resistance (129, 150, 151). Combining functional screens with metabolic analysis can also identify context-specific vulnerabilities that may be therapeutically actionable. A CRISPR (clustered regularly interspaced short palindromic repeats)–based loss-of-function screen identified GOT1, the cytosolic aspartate aminotransferase, as conditionally essential for survival during treatment with the ETC inhibitor phenformin (199). Isotope labeling then demonstrated that ETC blockade caused the direction of this enzyme to reverse from aspartate consumption in untreated cells to aspartate synthesis during ETC blockade (200). In addition to the discovery of synthetic lethality between ETC and GOT1 inhibition, these studies led to the novel biological concept that a major function of the ETC in proliferating cells is to support the synthesis of aspartate for nucleotide and protein synthesis (199, 200).
.Box 1: Key Principles and Lessons Learned • Reprogrammed metabolic pathways are essential for cancer cell survival and growth. • Frequently reprogrammed activities include those that allow tumor cells to take up abundant nutrients and use them to produce ATP, generate biosynthetic precursors and macromolecules, and tolerate stresses associated with malignancy (for example, redox stress and hypoxia). • An emerging class of reprogrammed pathways includes those allowing cancer cells to tolerate nutrient depletion by catabolizing macromolecules from inside or outside the cell (for example, autophagy, macropinocytosis, and lipid scavenging). • Reprogramming may be regulated intrinsically by tumorigenic mutations in cancer cells or extrinsically by influences of the microenvironment. • Oncometabolites (for example, D2HG) accumulate as a consequence of genetic changes within a tumor and contribute to the molecular process of malignant transformation. • Many metabolites exert their biological effects outside of the classical metabolic network, affecting signal transduction, epigenetics, and other functions. • New approaches to assess metabolism in living tumors in humans and mice may improve our ability to understand how metabolic reprogramming is regulated and which altered pathways hold opportunities to improve care of cancer patients.
pact on public health. It is clear that obesity and diabetes, both of which are reaching epidemic proportions in the developed world, increase cancer risk, but we lack insight into how to break these links.
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Cancer: fundamentals behind pH targeting and the double-edged approach.

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