New insights into molecules and pathways of cancer metabolism and therapeutic implications

Abstract

Cancer cells are abnormal cells that can reproduce and regenerate rapidly. They are characterized by unlimited proliferation, transformation and migration, and can destroy normal cells. To meet the needs for cell proliferation and migration, tumor cells acquire molecular materials and energy through unusual metabolic pathways as their metabolism is more vigorous than that of normal cells. Multiple carcinogenic signaling pathways eventually converge to regulate three major metabolic pathways in tumor cells, including glucose, lipid, and amino acid metabolism. The distinct metabolic signatures of cancer cells reflect that metabolic changes are indispensable for the genesis and development of tumor cells. In this review, we report the unique metabolic alterations in tumor cells which occur through various signaling axes, and present various modalities available for cancer diagnosis and clinical therapy. We further provide suggestions for the development of anti-tumor therapeutic drugs.

Keywords: cancer metabolism; metabolic pathway; metabolomic profiling; therapeutic implication.

FIGURE 1

Metabolic alterations in colorectal cancer. A. miR‐551a and miR‐483 induce CKB‐directed creatine phosphorylation and ATP‐sustaining liver colonization. B. LncRNA HOXB‐AS3‐encoded peptide alleviates the formation of PKM2 and downregulates glycolysis. C. SIRT5 activates GLUD1 and facilitates Gln to be incorporated into the TCA cycle. D. EGFR‐targeted cetuximab in combination with CB‐839 can improve therapeutic efficacy. E. BAs impair intestinal FXR and induce subsequent DNA damage. Abbreviations: CKB, creatine kinase brain‐type; LncRNA, long non‐coding RNA; PKM2, pyruvate kinase M2; SIRT5, sirtuin5; GLUD1, glutamate dehydrogenase 1; Gln, glutamine; TCA, tricarboxylic acid; EGFR, epidermal growth factor receptor; BA, bile acid; FXR, farnesoid X receptor;

FIGURE 2

Metabolic alterations in hepatocarcinoma. A. WTp53 downregulates pyruvate‐directed oxidative phosphorylation by triggering PUMA‐inactivated MPC. B. CUEDC2 triggers the GR‐GLUT3 peptide axis and 14‐3‐3ζ‐LDHA pathway to produce lactate. C. Lin28A and Lin28B express aberrantly while let‐7 downregulates, which contributes to activate PDK1 to TCA cycle. D. CD147 sustains the Warburg effect through PI3K/Akt/mTOR axis. E. TKT activates R5P and subsequent nucleotide production. F. mTORC2‐AKT axis triggers OXCT1 to drive ketolysis to the TCA cycle and inactivate AMPK. G. SNS regulates liver inflammation and secretory IL‐6 and TGF‐β production to trigger hepatocarcinogenesis. Abbreviations: WTp53, wild‐type p53; PUMA, p53 upregulated modulator of apoptosis; MPC, mitochondrial pyruvate carrier; CUEDC2, CUE domain‐containing protein 2; GR, glucocorticoid receptor; GLUT3, glucose transporter 3; LDHA, lactate dehydrogenase A; PDK1, pyruvate dehydrogenase kinase 1; TCA, tricarboxylic acid; TKT, transketolase; R5P, ribose 5‐phosphate; PPP, pentose phosphate pathway; mTORC2, mTOR complex 2; OXCT1, 3‐oxoacid CoA‐transferase 1; AMPK, AMP‐activated protein kinase; SNS, sympathetic nervous system; IL‐6, interleukin‐6; TGF‐β, transforming growth factor‐beta

FIGURE 3

The correlation between glucose metabolism and amino acid metabolism in tumor cells. Aerobic glycolysis contributes to serine metabolism, and glutamine metabolism and Warburg effect transmit precursors to the TCA cycle. Arginine is cleaved to produce urea and ornithine. Ornithine supports citrulline biosynthesis in the mitochondria, and subsequently to arginine renewal, and this series of reactions is termed as the urea cycle. And the urea cycle disorder and pentose phosphate pathway alter nucleic acid level. Abbreviations: G6PD, glucose‐6‐phosphate dehydrogenase; PHGDH, phosphoglycerate dehydrogenase; SDH, serine dehydratase; LDHA, lactate dehydrogenase A; IDO, indoleamine 2,3‐dioxygenase; IDH1, isocitrate dehydrogenase 1; GLUD1, glutamate dehydrogenase 1; GPT2, glutamic pyruvate transaminase 2; ASNase1, asparaginase 1; ASS1, argininosuccinate synthetase 1

FIGURE 4

Metabolic alterations in breast cancer. A. YAP‐upregulated lncRNA BCAR4 enhances the transcription of HK2 and PFKFB3 to generate lactate. B. TAM‐derived EVs deliver HISLA, which antagonizes the binding of PHD2 and HIF‐1α. C. Isocitrate/citrate enters the mitochondria via CTP and enables ROS stress downregulation. D. PHGDH improves serine levels and sustains purine and nucleotides biosynthesis. E. ADI‐PEG20 induces ASS1 deprivation and attenuates arginine synthesis with mitochondrial damage. F. UC disorder activates CAD and contributes to subsequent nucleic acid synthesis. G. SNS releases epinephrine to trigger LDHA and stabilize Myc, subsequently triggers SLUG and inactivates E‐cadherin. Abbreviations: YAP, Yes‐associated protein; LncRNA, long non‐coding RNA; BCAR4, breast cancer anti‐estrogen resistance 4; HK2, hexokinase 2; PFKFB3, 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3; TAM, tumor‐associated macrophage; EV, extracellular vesicle; HISLA, HIF‐1alpha‐stabilizing lncRNA; PHD2, prolyl hydroxylase 2; HIF‐1α, hypoxia‐inducible factor‐1 alpha; CTP, citrate transporter protein; ROS, reactive oxygen species; IDH2, isocitrate dehydrogenase 2; PHGDH, phosphoglycerate dehydrogenase; ADI‐PEG20, pegylated arginine deiminase; ASS1, argininosuccinate synthetase 1; UC, urea cycle; CAD, carbamoyl‐phosphate synthetase 2, aspartate transcarbamylase and dihydrooratase; SNS, sympathetic nervous system; LDHA, lactate dehydrogenase A

FIGURE 5

Metabolic alterations in non‐small cell lung cancer progression and metastasis. A. PD‐L1 triggers HK2 to promote the Warburg effect with immunosuppression. B. Lactate is driven to the TCA cycle via MCT1. C. PP1 to dephosphorylate AXIN and stimulates Wnt/β‐catenin axis. D. Nrf2 suppresses the heme‐induced and Fbxo22‐induced degradation of Bach1 through HMOX1. Abbreviations: PD‐L1, programmed death‐ligand 1; HK2, hexokinase 2; TCA, tricarboxylic acid; MCT1, monocarboxylate transporter‐1; PP1, RIF1 triggers protein phosphatase 1; AXIN, axis inhibition protein; HMOX1, heme oxygenase 1