Metabolic reprogramming in renal cancer: Events of a metabolic disease

Abstract

Recent studies have established that tumors can reprogram the pathways involved in nutrient uptake and metabolism to withstand the altered biosynthetic, bioenergetics and redox requirements of cancer cells. This phenomenon is called metabolic reprogramming, which is promoted by the loss of tumor suppressor genes and activation of oncogenes. Because of alterations and perturbations in multiple metabolic pathways, renal cell carcinoma (RCC) is sometimes termed as a "metabolic disease". The majority of metabolic reprogramming in renal cancer is caused by the inactivation of von Hippel-Lindau (VHL) gene and activation of the Ras-PI3K-AKT-mTOR pathway. Hypoxia-inducible factor (HIF) and Myc are other important players in the metabolic reprogramming of RCC. All types of RCCs are associated with reprogramming of glucose and fatty acid metabolism and the tricarboxylic acid (TCA) cycle. Metabolism of glutamine, tryptophan and arginine is also reprogrammed in renal cancer to favor tumor growth and oncogenesis. Together, understanding these modifications or reprogramming of the metabolic pathways in detail offer ample opportunities for the development of new therapeutic targets and strategies, discovery of biomarkers and identification of effective tumor detection methods.

Keywords: Cancer; Metabolic reprogramming; Metabolism; Renal cell carcinoma.

Figure 1.. Reprogramming of glucose transport and glucose metabolism in renal cancer

Glucose metabolism is comprised of glycolysis and pentose phosphate pathway (PPP) in the cytoplasm and TCA cycle in the mitochondria. Both glycolysis and PPP are upregulated in renal cell carcinoma (RCC). Glucose, transported in to the cells by GLUT and SGLT transporters, undergoes glycolysis to generate pyruvate which then goes through TCA cycle to generate ATP. In cancer cells, the flux of pyruvate entering TCA cycle decreases and the majority of pyruvate undergoes lactic acid fermentation for the rapid production of ATP. The MCT family of lactate transporters are upregulated in cancer cells, leading to increased efflux of lactate; and lactate accumulation results in an immunosuppressive extracellular environment. In cancer cells, increased PPP supplies the ribose sugar for the nucleotide synthesis necessary for rapidly growing cells. The oncogenes like HIF, AKT, STAT3 and EZH2 are known to influence the glucose transport and metabolism at multiple steps in RCC cells. The metabolites are depicted by squares and enzymes or transporters are denoted by ovals. Green arrows: Increase in activity, Red arrows: Decrease in activity. Abbreviations: ALDO, aldolase; ENO, enolase; EZH2, Enhancer of zeste homolog 2; FBP1, fructose-1-bisphophatase; Fructose-1,6-BP, fructose 1,6-bisphosphate; Fructose-6-P, fructose 6-phosphate; Glyceraldehyde-3-P, glyceraldehyde-3-phosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPI, glucose-6-phosphate isomerase; Glyceraldehyde-3-P, glyceraldehyde 3-phosphate; HK, hexokinase; LDH, lactate dehydrogenase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; PDK1, pyruvate dehydrogenase kinase; P-Enolpyruvate, phosphoenolpyruvate; PFK, phosphofructokinase; PGK, phosphoglycerate kinase; PGM, phosphoglycerate mutase; R5P, ribose-5-phosphate; TKT, transketolase; TPI, triosephosphate isomerase; 1,3-BP-Glycerate, 1,3-bisphospho-D-glycerate; GLUT1, glucose transporter-1; 2-P-Glycerate, 2-phosphoglycerate; 3-P-Glycerate, 3-phosphoglycerate; 6-P-Gluconolactone, 6-phosphoglucono-d-lactone; 6-P-Gluconate, 6-phosphogluconate; 6PGD, 6-phosphogluconate dehydrogenase; G6PD; glucose- 6-phosphate dehydrogenase; HIF, hypoxia inducible factor; MCT1, Monocarboxylate transporter 1; MCT4, Monocarboxylate transporter 4; SGLT2, sodium-glucose cotransporter 2; STAT3, Signal transducer and activator of transcription 3.

Figure 2.. Reprogramming of TCA cycle, fatty acid and glutamine metabolism in renal cancer

In RCC cells, both tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) are down-regulated. The mitochondrial biogenesis is also downregulated in RCC cells. In the context of the fatty acid metabolism, synthesis of fatty acid and lipids are up-regulated whereas β-oxidation of fatty acids is downregulated. Levels of carnitines, the fatty acid carriers, are also increased in RCC. Moreover, metabolites and enzymes in the cholesterol and phospholipid synthesis are also upregulated which leads to accumulation of lipid droplets, which gives the distinct clear histologic phenotype for clear cell renal cancer cells. In terms of glutamine metabolism, increased glutamine and upregulated reductive carboxylation pathway facilitate glutamine-dependent lipogenesis. Also, the glutathione/oxidized glutathione (GSH/GSSG) pathway for glutamine is upregulated to counteract the oxidative stress. The metabolites are depicted by squares and enzymes or transporters are denoted by ovals in the figures. Green arrows: Increase in activity, Red arrows: Decrease in activity. Abbreviations: ABAT, 4-aminobutyrate aminotransferase; ACAT, acetyl-CoA acetyltransferase; COX-2, cyclooxygenase-2; CPT1, carnitine palmitoyltransferase 1; FAS, fatty acid synthase; FH, fumarase; GABA, g-aminobutyric acid; GLS, glutaminase; GGT, γ-glutamyl transpeptidase; GST, glutathione-S-transferase; HADH, hydroxyacyl-CoA dehydrogenase; HETE, hydroxyeicosatetraenoic acid; IDH, isocitrate dehydrogenase; LOX-2, lipoxygenase-2; LPA, lysophosphatidic acid; MCAD, medium-chain specific acyl-CoA dehydrogenase; PA, phosphatidic acid; ROS, reactive oxygen species; SCD1, stearoyl-CoA desaturase-1; SCEH, short-chain enoyl-CoA hydratase; SDH, succinate dehydrogenase. VLCAD, very long-chain specific acyl-CoA dehydrogenase.

Figure 3.. Reprogramming of tryptophan metabolism in renal cancer

Tryptophan is metabolized through three major downstream pathways, the serotonin, indoleacetate, and kynurenine (KN) pathways. The kynurenine pathway of tryptophan metabolism is upregulated. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of the KN pathway is upregulated in renal cancer cells; and increased kynurenine in the tumor microenvironment suppresses immune cell activation and facilitates immune evasion of renal cancer cells. The metabolites are depicted by squares and enzymes or transporters are denoted by ovals in the figures. Green arrows: Increase in activity, Red arrows: Decrease in activity. Abbreviations: ALDH2, aldehyde dehydrogenase 2; DDC, DOPA decarboxylase; MAO, monoamine oxidase; QN, quinolinate.

Figure 4.. Reprogramming of arginine Metabolism in renal cancer

Arginine metabolism in cancer cells involves both urea cycle and TCA cycle. Normal cells synthesize arginine from citrulline through the urea cycle. Argininosuccinate synthase-1 (ASS1), the enzyme responsible for arginine synthesis in the urea cycle, is often downregulated in RCC. Thus, renal cancer cells are heavily dependent on external arginine supply for growth and survival. Through the synthesis of Fumarate from Arginosuccinate, an intermediate in the urea cycle, Arginine can enter through TCA cycle; however, this pathway is often downregulated in RCC cells due to lack of arginine synthesis and decreased ASS1 expression. The metabolites are depicted by squares and enzymes or transporters are denoted by ovals in the figures. Red arrows: Decrease in activity. Abbreviations: OCT, ornithine carbamoyl transferase.

Figure 5.. Overview of altered metabolic events in renal cell carcinoma (RCC)

A summarization of metabolic reprogramming or altered metabolic events in renal cell carcinoma (RCC). Inactivation of the tumor suppressor gene VHL through deletion or mutation is a key factor for the metabolic reprogramming in RCC cells. Loss of VHL leads to the deregulation of the hypoxia-inducible factor (HIF) family of transcription factors and other oncogenic signaling events, including the hyperactivation of Ras-phosphoinositide 3-kinase (PI3K)–AKT–mechanistic target of rapamycin (mTOR) pathway(s); they contribute to the reprogramming of multiple metabolic events in renal cancer cells. In RCC cells, upregulation of glucose transporters (GLUT or SGLT) increase glucose uptake and is catabolized through an elevated aerobic glycolysis (Warburg effect) and lactate fermentation. The upregulated pentose phosphate pathway provides reducing equivalents (NADPH) to inhibit the oxidative stress and ribose precursors for nucleotide synthesis needed for the rapidly growing cells. Increased efflux of lactate contributes to an immunosuppressive tumor microenvironment. The TCA cycle is downregulated in renal cancer cells due to lower conversion rate of pyruvate to acetyl-CoA and suppression of intermediates like fumarate and α-ketoglutarate. In RCC, lipid synthesis predominates over lipid degradation. The β-oxidation pathway of lipids is downregulated and contains the levels of acetyl-CoA to feed the TCA cycle. However, the synthesis of carnitine, fatty acids, phospholipids and cholesterol are upregulated in RCC. Urea cycle is downregulated in renal cancer cells which decreases the catabolism of amino acids like arginine and glutamine. The RCC cells take up increased amounts of glutamine for the synthesis of fatty acids through reductive carboxylation. The elevated glutamine in RCC also adds to the upregulated glutathione/oxidized glutathione (GSH/GSSG) pathway to neutralize the oxidative stress and reactive oxygen species (ROS). Metabolism of the amino acid tryptophan through the kynurenine (KN) pathway is upregulated to generate an elevated level of immunosuppressants like kynurenine and quinolinate. Thus, reprogramming of metabolic pathways produces energy (ATP) and other molecules like lipids, phospholipids and ribose sugars essential for cellular proliferation and enables renal cancer cells to endure hypoxia, nutrient exhaustion and oxidative stress, as well as evade the immune system for survival.