Metabolic Reprogramming in Cancer Cells: Emerging Molecular Mechanisms and Novel Therapeutic Approaches

Abstract

The constant changes in cancer cell bioenergetics are widely known as metabolic reprogramming. Reprogramming is a process mediated by multiple factors, including oncogenes, growth factors, hypoxia-induced factors, and the loss of suppressor gene function, which support malignant transformation and tumor development in addition to cell heterogeneity. Consequently, this hallmark promotes resistance to conventional anti-tumor therapies by adapting to the drastic changes in the nutrient microenvironment that these therapies entail. Therefore, it represents a revolutionary landscape during cancer progression that could be useful for developing new and improved therapeutic strategies targeting alterations in cancer cell metabolism, such as the deregulated mTOR and PI3K pathways. Understanding the complex interactions of the underlying mechanisms of metabolic reprogramming during cancer initiation and progression is an active study field. Recently, novel approaches are being used to effectively battle and eliminate malignant cells. These include biguanides, mTOR inhibitors, glutaminase inhibition, and ion channels as drug targets. This review aims to provide a general overview of metabolic reprogramming, summarise recent progress in this field, and emphasize its use as an effective therapeutic target against cancer.

Keywords: carbohydrates; energy metabolism; immunotherapy; inflammation; metabolic reprogramming; neoplasms; tumor microenvironment.

Figure 1

Carbohydrate metabolism and mediators of metabolic reprogramming. Cancer cells must acquire a greater amount of nutrients, especially glucose. One of the mediators is HIF-1, which increases glucose uptake through the induction of GLUT-1, GLUT-4 and GLUT-1; simultaneosly, it can also be stimulated by TGF-β through the PI3K/AKT/mTOR pathway. Other important mediators are p53 that plays a protective role against ROS. GLUT, glucose transporters; Glu-6-P, glucose 6-phosphate; Fru-6-P, fructose 6-bisphosphate; Fru-1,6-P, fructose 1,6-bisphosphate; Fru-2,6-P, fructose 2,6-bisphosphate; GA-3-P, glyceraldehyde 3-phosphate; PEP, phosphoenolpyruvate; HK, hexokinase; TGFB, transforming growth factor beta; PFK1, phosphofructokinase 1; PKM2, pyruvate kinase M2; LDHA, lactate dehydrogenase A; G6PD, glucose-6-phosphate dehydrogenase; 6-PGL, 6-phosphogluconolactonase; NADP+, nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of NADP; GSSG, glutathione disulfide; GSH, glutathione; H₂O₂, hydrogen peroxide; TIGAR, Tp53-induced glycolysis and apoptosis regulator; FGF, fibroblast growth factor; HIF-1, hypoxia-inducible factor 1; PPP, pentose phosphate pathway; KRAS, Kirsten-ras; RPIA, ribose-5 phosphate isomerase; MYC, proto-oncogene; Ribulose-5-P, ribulose 5-phosphate; Ribose-5-P, ribose 5-phosphate; SGLT1/2, sodium-glucose cotransporter-1/2.

Figure 2

Lipids metabolism and mediators of metabolic reprogramming. Lipid metabolism in cancer cells is altered to increase the availability of these molecules, which provide structural components for the cell membrane, second messengers, and a fuel source. Fatty acids enter the cell by several pathways, including LDRL-mediated endocytosis and a wide variety of membrane transporters, such as CD36 and FABP1-6. Another source of FAS is lipogenesis. Once in the intracellular space, FAS can be stored in the cellular FAS pool by means of FABP 3/4/7, and can also serve as a substrate for the formation of MUFA, PUFA, TAG, etc. Likewise, some authors suggest FAS are a great energy source through β-oxidation and act as donors of acetyl and methyl groups, participating in epigenetic modifications. In cancer, there is an increase in the expression of enzymes involved in lipogenesis, cholesterol synthesis, and beta-oxidation, such as ACC, FASN, ACLY, and CPT1C, where the latter is due to p53. LDRL, low-density lipoprotein receptor; CD36, a cluster of differentiation 36; FABP, fatty acid-binding protein; FAS, fatty acids synthetase; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; TAG, triacylglycerides; CPT1C, carnitine palmitoyltransferase 1C; FASN, fatty acid synthase; ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; ↑, increase.

Figure 3

Protein metabolism and mediators of metabolic reprogramming. Protein metabolism in cancer cells is altered due to the immense demand generated by constant cell division, which is why amino acids are of great importance as proteogenic building blocks. Among the amino acids, glutamine is of great relevance in cancer cells. Glutamine enters the cell by different pathways, including macropinocytosis (which is increased by mutated RAS and c-SRC), entosis, degradation of cell-matrix proteins by metalloproteases, and transport by SLC1A5. Glutamine serves as a nitrogen donor and is used to synthesise nucleotides, purines, and proteins. It can also be a source of energy through glutaminolysis, which p53 and c-Myc stimulate. When there is a decrease in glutamine levels, it is synthesized by GLUL using glutamate as a substrate. Likewise, glutamine intervenes indirectly in the redox balance through glutamate. Serine is also essential, since increases in serine and 3-phosphoglycerate dehydrogenase, the first enzyme involved in its synthesis, are associated with tumor growth. Serine feeds carbon metabolism and protein synthesis, favors the synthesis of the oncometabolite 2-hydroxy-glutarate, and can act as an energy source, since it is an anaplerotic metabolite. In addition, methionine and SAM facilitate the pattern of histone methylation in monocytes/macrophages and the activation of TAMs. Depletion of exogenous methionine promotes tumor growth, metastasis, and immune evasion. SLC1A5 solute transporter family member 5; PPAT, phosphoribosyl pyrophosphate amidotransferase; PRA, phosphoribosylamine; GLS, glutaminase; GLUL, glutamine synthetase; AKG, alpha-ketoglutarate; SAMs S-adenosylmethionine; MAT, methionine adenosyltransferase; TAMs, tumor-associated macrophages.

Figure 4

Role of hypoxia inducible factor-1 in cancer cell metabolic reprogramming. Hypoxia modifies cell metabolism through the expression of HIF-1α, which influences tumor angiogenesis, cancer cell migration, invasion, and glycolytic metabolism. In addition to this, HIF-1α can be activated by TGF-β action via the PI3K/AKT/mTOR pathway, and at the same time, HIF-1α can activate TGF-β in a positive feedback loop. Among the most important metabolic changes produced by HIF-1α are increased glucose uptake, glycolysis, and decreased glucose oxidation through the induction of GLUT 1/4/8, PKF, HK 1/2, and PGK1. There is also an increase in lactate and NAD+ production through LDH. Together, an increase in MCT4 expression contributes to lactate efflux. Another effect of HIF-1α expression is the suppression of mitochondrial function, resulting from inactivation of the TCA cycle, inhibition of PGC1 β, and repression of ISCU 1/2 by miR-210. Finally, HIF-1α promotes abnormal fatty acid synthesis through overexpression of FASN, which is mediated by increased SREBP-1 activation. HIF-1α, hypoxia-inducible factor-1; TGF-β, transforming growth factor beta; PI3K, phosphoinositol 3-kinase; LDH, lactate dehydrogenase; NAD, nicotinamide adenine dinucleotide; MCT4, monocarboxylate transporter 4; GLUT, glucose transporter; PKF, phosphofructokinase; PGK1, phosphoglycerate kinase 1; HK, hexokinase; PDK, phosphoinositide-dependent kinase; TCA, tricarboxylic acid; PGC1 β, peroxisome proliferator-activated receptor-gamma coactivator-1 beta; miR-210, microRNA-210; ISCU, iron-sulfur group; SREBP-1, sterol regulatory element binding protein 1; FASN, fatty acid synthase; ↑, increase; ↓, decrease.