cancer cells metabolism

Introduction

Metabolic activities are altered in cancer cells relative to healthy cells. Glycolysis, the TCA cycle, the ETC, and the pentose phosphate pathway, as well as lipid metabolism pathways, have all been shown to be altered in tumor cells. Alterations are to support bioenergetics, biosynthesis, and redox balance. Reprogrammed activities improve cellular fitness to provide a selective advantage during tumorigenesis and support cell survival under stressful conditions. Mutations of oncogenes and tumor- suppressor genes can modify multiple intracellular signaling pathways and, in turn, alter cell metabolism to facilitate the tumorigenic process. Loss of tumor suppressors and activation of oncogenes alleviates the necessity of having mutations or amplifications in metabolic enzymes.

Glycolysis, the TCA cycle, the ETC, and the pentose phosphate pathway, as well as lipid metabolism pathways, have all been shown to be altered in tumor cells and to play a role in tumorigenesis. Cancer cells exhibit high rates of glycolysis and lactate fermentation. Otto Warburg effect is the conversion of glucose to lactate persists in malignant tumors despite the presence of oxygen. Aerobic glycolysis in cancers, is the combined result of oncogenes, tumor suppressors, a hypoxic microenvironment, mtDNA mutations, and others. In most solid tumor cells, a switch in metabolism towards glycolysis over respiration despite their functional oxidative phosphorylation machinery manifests the cancer-specific aerobic glycosis. Glutamine is an essential bioenergenic and anabolic substrate for many cancer cell types. It is used to provide intermediates of the tricarboxylic acid (TCA) cycle to feed other biosynthesis pathways as precursors (Wise et al., 2011).

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 up new biomass. Some cancer cells survive and even grow during primary nutrient starvation by maintaining metabolic activity through catabolizing both intracellular and extracellular macromolecules. This metabolic ‘scavenging’ appears essential for the growth of a subset of tumors. A new understanding of cancer metabolic profiles provide a hope that a new class of therapeutic agents may be developed for cancer therapy. Therefore, effective use of metabolic inhibitors may provide a clinically favorable therapeutic strategy. This report will review the reprograming cancer cell metabolism and signalling pathways that regulate cancer metabolism.

Signalling pathways

Cell metabolism is regulated by signalling pathways related to oncogenes and tumor-suppressor genes. Cancer cell metabolism is a direct result of the modulation of intracellular signalling pathways that are disrupted by mutated oncogenes and tumor-suppressor genes. The reprogramming in metabolic activities is to meet the bioenergetics, biosynthetic, and redox demands of malignant cells and to support main properties. Glycolysis, the TCA cycle, the ETC, and the pentose phosphate pathway, as well as lipid metabolism pathways, have all been shown to be altered in tumor cells and to play a role in tumorgenesis. Activation of oncogenes like MYC promotes anabolism through transcriptional regulation of metabolic genes. Myc was shown to regulate glycolysis in cells grown under normoxic conditions though it increases the expression of Pyruvate dehydrogenase kinase (PDK1), lactate dehydrogenase (LDH) and monocarboxylate transporter (MCT1). LDH is an enzyme that catalyzes the reductive conversion of pyruvate to lactate, whereas monocarboxylate transporter (MCT1), which facilitates the efflux of lactate into the extracellular space. Also, Myc enhances the glycolytic pathway by increasing transcription of glycolytic enzymes and also involved in glutamine metabolism. It has been shown that the transcription of factor C-Myc is a principal driver of glutamine utilization by proliferating cells (Wang et al., 2011b; Wise et al., 2008). C-myc induces the transcription of glutamine transporters ASCT and SN2, and it, however, promotes the expression of glutamine –utilizing enzymes glutaminase (GLS1), phosphoribosyl pyrophosphate synthetase (PRPS2), and carbamoyl phosphate synthetase 2 (CAD), which support transporter –facilitated glutamine uptake by converting glutamine to glutamate(Eberhardy and Farnham,2001; Gao et al.,2009).

In healthy cells, P53 suppresses glycolysis by increasing the expression of TIGAR, supporting the expression of PTEN, and promoting oxidative phosphorylation via cytochrome c oxidase. P53 directly stimulates oxidative phosphorylation through up-regulation of cytochrome c oxidase 2 (SCO2), which is required for the assembly of the cytochrome c oxidase complex of the electron transport chain. Hence, loss of p53 shifts metabolism from mitochondrial respiration towards glycolysis. Also, the loss of PTEN increases glycolysis by activation of AKT and HIF-1.

Also, mutant Ras provides cells with a mechanism that allows them to recover free amino acids through the liposomal degradation of extracellular proteins (Commisso et al., .2013). Also, it induces transcriptional upregulation of enzymes that mediates ribose -5- phosphate biosynthesis (Son et al., 2013). Oncogene mutation of Ras activates mTOR via the PI3K-Akt- mTOR signalling pathway, which acts as a master regulator for glucose uptake. In the P13K/AKT/mTOR pathway, AKT is an essential driver of the tumor glycolytic phenotype and stimulates ATP generation. AKT stimulates glycolysis by increasing the expression of glucose transporters and by phosphorylating key glycolytic enzymes, such as hexokinase and phosphofructokinase. Akt phosphorylation of apoptotic proteins such as Bax makes cancer cells resistant to apoptosis and helps stabilize the outer mitochondrial membrane (OMM) (Guo et al., 2009). Activated mTOR indirectly causes metabolic changes to stimulate protein and lipid biosynthesis and cell growth through activating transcription factors such as hypoxia-inducible factor 1 (HIE1A). HIF-1 regulates many different genes, such as vascular endothelial growth factor, hepatocyte growth factor receptor, and erythropoietin transforming growth factor –x, platelet-derived growth factor-β, and glucose transporter GLUTI and therefore influences such cellular activities as angiogenesis, glycolysis, and cell survival. Also, HIF-1 activates pyruvate dehydrogenase kinases (PDKs), thereby inactivation pyruvate dehydrogenase and blocking the flow of pyruvate into the TCA cycle, decreasing oxygen consumption.

Fig. 1

Signaling pathways that regulate cancer metabolism ( DeBerardinis and Chandel, 2016 ).

Aerobic glycolysis

Two principle nutrients that support survival and biosynthesis in mammalian cells are glucose and glutamine. 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. Most mammalian cells use glucose as a fuel source. However, cancer cells only partially break down sugar molecules through glycolysis; this results in only two molecules of ATP per each glucose molecule. Cancer cells convert much of the pyruvate into lactate. However, the catabolism of glucose into lactate has a meager energy yield. Tumor cells possess functional mitochondria and retain the ability to conduct oxidative phosphorylation. As a result, cancer cells need to use a lot more sugar molecules to get enough energy to survive.

Glycolytic intermediates leave glycolysis to take part in diverse biosynthesis reactions. Accordingly, the rate-limiting enzymes within branching pathways of glycolysis are frequently up-regulated in tumors. The increase in glycolytic flux allows glycolytic intermediates to supply subsidiary pathways to fulfill the metabolic demands of proliferating cells (Lunt and Vander-Helden, 2011). Excess glucose is diverted through the pentose phosphate shunt (PPP) and serine/glycine biosynthesis pathway to create nucleotides.

Like glycolytic, tricarboxylic acid (TCA) cycle intermediates are also used as precursors for macromolecules synthesis (Ahn and Metallo, 2015). Their utilization in biosynthetic pathways requires that carbon be resupplied to the cycle so that intermediate pools are maintained. Tumor cells generate TCA cycle intermediates that can enter the cycle at sites other than acetyl-CoA (coenzyme A) (Owen, Kalhan, and Hanson, 2002). Tumor cells very frequently contain mutations that allow the P13K -AKT-mTOR network to achieve high levels of signalling with minimal dependence on extrinsic stimulation by growth factors (Yuan and Cantley, 2008). activated phosphatidylinositol 3-kinase (PI3K) and its downstream pathways AKT and target of rapamycin (mTOR) are promoting increased glycolytic flux and fatty acid synthesis through activation of hypoxia-inducible factor-1 (HIF-1) and sterol regulatory element-binding protein (SREBP) (Dibble and Manning, 2013).

Otto Warburg effect

In the 1920s, Otto Warburg, a German scientist, and psychologist was the first to describe this unusual behavior of cancer cells. Otto Warburg observed that tumor constitutively take up glucose and produce lactate regardless of oxygen availability. Warburg’s observation that tumors display a high rate of glucose consumption has been validated in many human cancers. Pyruvate from glycolysis is directed away from the mitochondria to create lactate through the action of lactate dehydrogenase. Also, cancer cells did not take advantage of the bioenergetics benefits offered by the coupling of glycolysis to the TCA cycle. An abnormal dependence on glycolysis as the sole source of ATP creation, even in the presence of oxygen, is seen in many cancer cells and is commonly called the ‘ Warburg effect’ (Warburg, 1956). In simple terms, it is the production of lactate in the presence of oxygen. Warburg effect is a regulated metabolic state and may be beneficial during a time of increased biosynthetic demand (Koppenol, Bounds and Dang, 2011).

TCA cycle and Oxidative phosphorylation (in cancer cells )

Pyruvate flux through the TCA cycle is down-regulated in cancer cells or compromised by hypoxia, ETC impairment. Cells harboring mutations in FH or SDH still rely on mitochondrial metabolism by metabolically rewiring themselves to provide the necessary TCA cycle intermediates and ROS for cell proliferation (Adam et al., 2011). Also, these mutations cause a disruption of the TCA cycle with the accumulation of fumarate or succinate, resulting in inhibition of dioxygenases or prolyl hydrolases that mediate the degradation of HIF proteins. Multiple inputs into the TCA cycle allows cancer cells to adequately respond to the fuels available in the changing microenvironment during the evolution of the tumor (Borough, and Deberordinis, 2015). glutamine can provide acetyl-CoA as a biosynthetic precursor to sustain tumor growth (Adam et al., 2011). The BCAAs isoleucine, valine, and leucine, which are elevated in the plasma of patients with pancreatic cancers, can be converted into acetyl-CoA and other organic molecules that also enter the TCA cycle (Mayers et al., 2014).

Glutamine biosynthesis

Glutamine, a second principal growth-supporting substrate, contributes not only carbon but also reduced nitrogen for the de novo biosynthesis of several diverse nitrogen-containing compounds. Also, glutamine has been reported to play a role in the uptake of essential amino acids. The import of an essential amino acid antiporter LAT1 was shown to be coupled efflux of glutamine (Nicklin et al., 2009). Intracellular glutamine facilitates a broad range of LAT1 substrates, including leucine, isoleucine, valine, methionine, tyrosine, tryptophan, and phenylalanine (Yanagida et al., 2001). The glutaminase enzyme converts glutamine to glutamate, which can be used to make alpha-ketoglutarate, a critical intermediate in the TCA cycle. The TCA cycle intermediates are used in the synthesis of nucleic and fatty acids. Tumor cells have been commonly shown to have higher levels of dependence on glutamine, which is a source of nitrogen for the synthesis of nucleotides and amino acids (Pavlova and Thompson, 2016). The transcription factor c-myc is a principal driver of glutamine utilization by proliferating cells (Wang et al., 2011b; Wise et al., 2011). C-myc induces the transcription of glutamine transporters ASCT2 and SN2 and promotes the expression of glutamine-utilizing enzymes glutaminase (GLS1), phosphoribosyl pyrophosphate synthetase (PRPS2), and carbamoyl phosphate synthetase 2 (CAD), which support transporter-facilitated glutamine uptake by converting glutamine to glutamate (Eberhardy and Farnham, 2001; Gao et al., 2009). Cancer cells frequently use glutamine as another fuel source, which enters the mitochondria. It can be used to replenish Krebs Cycle intermediates or to produce more pyruvate through the action of malic enzyme (Nicklin et al., 2009).

Serine biosynthesis (and what does cancer use it for ? )

Serine is the third most consumed metabolite by cancer cells after glucose and glutamine. Serine is utilized in the biosynthesis of the thymidine monophosphate and purines. Serine metabolism supplies methyl groups to the one-carbon and folate pools contributing to nucleotide synthesis, methylation reactions, and NADPH (nicotinamide adenine dinucleotide phosphate) production. A significant amount of serine is converted into glycine through the activity of cytosolic or mitochondrial serine hydro methyltransferases (SHMT1 and SHMT2). The non-essential amino acid serine can be either imported from the medium or synthesized from the glycolyte by 3PG dehydrogenase (PHGDH), an enzyme that is often genetically amplified in cancers. The elevated expression of phosphoglycerate dehydrogenase (PHGDH) catalyzes the conversion of the glycolytic intermediate 3-phosphoglycerate to 3-phosphohydroxypyruvate in the first step of the serine biosynthesis pathway (Possemato et al., 2011; Locasale et al., 2011). Researches have been shown that inhibiting serine biosynthesis by silencing PHGDH in cells with high levels of this enzyme results in growth suppression (Possemato et al., 2011; Locasale et al., 2011).

Methionine cycle

Methylation processes are crucial for epigenetic regulation of gene expression. The essential amino acid methionine can be either imported into cells or recycled through the methylation cycle. In the canonical methylation cycle, methionine is converted into S-adenosyl-methionine (SAM) through the activity of methionine adenosyltransferase transferase (MAT). Here SAM provides a methyl group and is converted into S-adenosylhomocystein (SAH). SAH is then hydrolyzed to adenosine and homocysteine. Finally, methionine synthase transfers a one-carbon unit from 5-methyl-THF to homocysteine, thereby regenerating methionine.

fig2: the methionine and homocysteine cycle.

ROS signalling and hypoxia (in cancer cells and the microenvironment)

The blood vessels (vasculature) in a tumor are not formed properly and are often twisted and in abnormal (Convoluted) looking. The defective structure leads to a reduced ability to deliver oxygen and results in the development of acidic conditions. Some parts of the tumor are far from blood vessels and do not receive enough nutrients and oxygen. As tumors grow in size, they can outgrow their blood supply, and This results in the area inside the tumor becoming very low in oxygen (hypoxic). The tumor cell proliferation rate often exceeds the rate of new blood vessel formation (angiogenesis). The harsh tumor microenvironment showed increases ROS levels and low glucose levels, which limit glucose flux through the cytosolic oxidative PP, thus decreasing cytosolic NADPH levels. Also, with reduced use of oxygen and the rapid energy production, there is a notable shift in mitochondrial function from an energy producer to a creator of biosynthesis intermediates. Also, mitochondrial oxygen metabolism is linked to the generation of reactive oxygen species (ROS)( Sabharwal and Schumacker, 2014), which at a high level, can damage nucleotides, proteins, and lipids, so impairing viability.

ROS are intracellular chemical species that contain oxygen and include the superoxide anion, hydrogen peroxide, and the hydroxyl radical. Cancer cells have an increased rate of spatially localized mitochondria and ROS production compared to healthy cells. ROS has been thought of as lethal metabolic by-products of cellular respiration and protein folding. Furthermore, studies showed the role of ROS in cellular signalling. ROS-mediated activation of death-inducing pathways. During tumorigenesis and metastasis, redox homeostasis is required accordingly, to prevent toxic levels of ROS, tumor cells increase their antioxidant capacity to allow for cancer progression (Sabharwal and Schumacker, 2014). To counteract, these cells level different pathways for ROS detoxification. The proximal activation of signal pathways (P13K and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and transcription of factors (HIF and nuclear factor-kB(NF-kB) necessary for tumorigenesis (Xu et al., 2011).

Cells in nutrient-deprived conditions activate AMPK to increase NADPH levels by stimulating PPP-dependent NADPH and diminishing anabolic pathways, such as lipid synthesis. ROS turnover through the pathway requires a supply of NADPH. NADPH can be generated from glucose from the reduced phosphate pathway or serine via one-carbon metabolism. Cancer cells increase their antioxidant capacity is by activating the transcription factor nuclear factor. To maintain the antioxidant capacity of GPXs and TXNs, NADPH is required. In cancer cells, glutathione (GSH) coupled to NADPH reduction-oxidation is a significant pathway for ROS detoxification. GSH oxidation by GSH peroxidase is coupled to the turnover of hydrogen peroxide (H2O2), a major ROS by-product of mitochondrial oxidative phosphorylation. Oxidized glutamate (GSSC) is then reduced back to GSH by GSH reductase coupled to NADPH oxidation.

Hypoxic adaptation essential for survival and progression of a tumor is thought to be closely linked to metabolic changes in cancer cells. In response to hypoxic conditions, a protein induced factor 1-alpha (HIF1-alpha) is activated. Activation of HIF-1 is through a variety of mechanisms, including (i) hyperactivation of mTOR (ii) accumulation of ROS (iii) accumulation of the TCA cycle metabolites succinate or fumarate due to cancer-specific mutations in succinate dehydrogenase (SDH) or fumarate hydratase (FH). The HIF1-alpha protein increases the rate of glycolysis. Low oxygen levels help to promote cell movement and cancer spread (metastasis) by causing the production of TWIST, a protein that plays an essential role in metastasis.

Macromolecule biosynthesis (proteins, lipids

and nucleic acids )

The acquisition of simple nutrients (sugars, essential amino acids, etc), from extracellular space followed by their conversion into biosynthetic, intermediates through core metabolic pathways like glycolysis, the PPP, the TCA cycle, and non-essential amino acid synthesis, and finally the assembly of larger and more complex molecules through ATP-dependent processes. Biosynthesis of all three classes is under the control of the same signalling pathways that govern cell growth and are activated in cancer via tumorigenic mutations, particularly P13K- mTOR signalling which induces an anabolic growth program resulting in nucleotides, protein and lipid biosynthesis.

P13K -AKT-mTOR signalling pathway is mediating activation of protein Synthesis (Guo et al., 2011). Protein biosynthesis is under the influence of growth factor, which signalling and expressing surface transporters that allow the cell to acquire amino acids from the extracellular space. Most non-essential amino acids are produced through glutaminolysis, which produces α-ketoglutarate from glutamine or through transamination reactions, which transfers the amino group from glutamate to ketoacid. Proliferating cancer cells, both through glutamine uptake and glutamines activity, are stimulated by mTORC1.

Autophagy supplies amino acids through protein degradation. Protein degradation pathways have been characterized extensively as mechanisms to supply amino acids in cancer cells. Intracellular proteins and other macromolecules can be recycled through autophagy, a highly regulated process through which proteins and organelles are derived to the lysosome and degraded.

Tumor cells rapidly produce fatty acids for membrane biosynthesis and lipidation reactions. Fatty acids and amino acids can supply substrates to the TCA cycle to sustain mitochondrial ATP production in cancer cells. Both fatty acids and lipids can also be acquired from the extracellular space to supply membrane biosynthesis. Fatty acid synthesis requires sources of acetyl CoA and cytosolic NADPH; practical fatty acid synthesis hence requires integration with other pathways of carbon and redox metabolism. Glucose is the most prominent acetyl –CoA source for fatty acid synthesis.

Glutamine and acetate provide alternative carbon sources when access glucose-derived acetyl–CoA is impaired by hypoxia. Isotopic tracing experiments showed that most NADPH used for fatty acid synthesis arises from the PPP. Pl3k signalling activates fatty acid uptake and suppresses fatty acid oxidation, thereby maximizing lipogenesis in proliferating cells under the control of growth factors. Oncogenic activation of epidermal growth factor receptor (EGFR) signalling stimulates SREPB-1. In cancer cells with constitutively high rates of fatty acid synthesis, additional mechanisms help keep SREBP-1 in a transcriptionally active state. mTORC signalling activates a transcriptional program that includes both SREBP-1 and the related protein SREBP-2.

De novo biosynthesis of nucleotides is complex, requiring input from several pathways in a coordinated fashion. The phosphoribosylamine backbone of these molecules is produced from ribose-5-phosphate, an intermediate of the PPP, and an amide donation reaction using glutamine as a substrate. TCA cycle contributes oxaloacetate transmitted to aspartate required to synthesize both purine and pyrimidine bases. Well-characterized mechanisms of feedback inhibition exist to prevent excessive accumulation of nucleotides, interrupting these mechanisms can produce pathological accumulation of nucleotide intermediates (precipitation of uric acid crystals in gout).

Targeting metabolic pathways and metabolites in cancer for cancer therapy

Many research efforts have been conducted to identify small molecules that might specifically inhibit key metabolic steps associated with tumor growth. There are a few things to consider when determining what makes an excellent metabolic target for cancer therapy. First, inhibition of some metabolic enzymes is likely to be systemically toxic because of their physiological functions in healthy tissues (Erez and DeBerardinis, 2015). The feasibility of targeting these pathways therapeutically depends on whether the systemic blockade of the pathway can be tolerated. Second, healthy proliferating cells, such as immune cells and stem cells, also reprogram their metabolism in a manner similar to cancer cells (Pearce, Poffenberger, Chang and Jones, 2013; Ito and Suda, 2014). Metabolic inhibitors should likely not interfere with the adaptive immune system. To date, many of the genetic and pharmacologic interventions on metabolic enzymes have been conducted using human cancer cells subcutaneously injected into athymic mice.

Nevertheless, it will be necessary for future experiments to not only use patient-derived xenograft (PDX) models but also make use of genetically engineered mouse cancer models and syngeneic mouse models that have intact immune systems, especially given the promising results from immunotherapy. Third, alterations in metabolite levels can affect cellular signalling, epigenetics, and gene expression through posttranslational modifications such as acetylation, methylation, and thiol oxidation. Cancer cells could develop resistance to inhibition of a particular metabolic pathway by expressing alternate protein isoforms or up-regulating compensatory pathways. Thus, it is critical to elucidate in normal cells any toxic effects of metabolic enzyme inhibition. To circumvent this challenge, one approach is to target a metabolic enzyme in a deregulated pathway specific to cancer cells. Fifth, metabolic phenotypes depend not only on the tumor’s genetic driver but also on the tissue of origin. For instance, MYC stimulated glutamine catabolism in liver tumors, whereas MYC-driven lung tumors expressed glutamine synthetase and accumulated glutamine ((Yuneva et al., 2012)). Thus, in vivo isotope tracing can detect metabolic activities of intact tumors and characterize some of the factors that specify the metabolic phenotype.

Enhanced nucleotide and DNA synthesis in tumor cells is targeted by antifolates (methotrexate, pemetrexed, and others) (Vander Heiden, 2011). Although these drugs do produce toxicity in healthy proliferative tissues like the intestinal epithelium and bone marrow, they are essential components of highly successful chemotherapeutic regimens. Lactate dehydrogenase (LDH) is another enzyme essential for tumor cell metabolism. LDH catalyzes the conversion of pyruvate to lactate. The reduction step is necessary for the regeneration of NAD, which is needed to continue glycolysis. It has been observed that decreases in LDH inhibits glycolysis and has antitumor effects in cancer cells. Mitochondrial metabolism has also emerged as a critical target for cancer therapy ((Weinberg and Chandel, 2014). Numerous epidemiological studies first suggested that diabetic patients taking metformin, to control their blood glucose levels, were less likely to develop cancer and had an improved survival rate if cancer was already present (Evans et al., 2005). Biochemists recognized that metformin reversibly inhibits mitochondrial complex I ((Bridges, Jones, Pollak and Hirst, 2014; Owen, Doran and Halestrap, 2000). Recent studies indicate that metformin acts as an anticancer agent by inhibiting mitochondrial ETC complex I (Wheaton et al., 2014). Specifically, metformin inhibits mitochondrial ATP production, inducing cancer cell death when glycolytic ATP levels diminish as a result of limited glucose availability. Another potential therapeutic strategy to inhibit mitochondrial metabolism in certain tumors would be to use autophagy or glutaminase inhibitors. Autophagy provides amino acids, such as glutamine, that fuel the TCA cycle.

An additional therapeutic approach is to target redox metabolism, that is, selectively disable the antioxidant capacity of cancer cells causing ROS levels to rise and induce cancer cell death (Gorrini, Harris and Mak, 2013). An exciting 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. ( DeBerardinis and Chandel, 2016 ).

Conclusion

Metabolic reprogramming is essential for the biology of malignant cells, particularly their ability to survive and grow by using conventional metabolic pathways to produce energy, synthesize biosynthetic precursors, and maintain redox balance. Metabolic reprogramming is the result of mutations in oncogenes and tumor suppressors, leading to activation of PI3K and mTORC1 signaling pathways and transcriptional networks involving HIFs, MYC, and SREBP-1. Alterations in metabolite levels can affect cellular signaling, epigenetics, and gene expression through posttranslational modifications such as acetylation, methylation, and thiol oxidation. Taken together, studies on cultured cells have demonstrated a remarkable diversity of anabolic and catabolic pathways in cancer, with the induction of autophagy and utilization of extracellular lipids and proteins complementing the classical pathways like glycolysis and glutaminolysis.