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Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

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Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance H OH metabolites OH Review Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance Xun Chen 1, Shangwu Chen 2,* and Dongsheng Yu 1,* 1 Guangdong Provincial Key Laboratory of Stomatology, Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510055, China; [email protected] 2 Guangdong Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory for Biocontrol, Department of Biochemistry, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China * Correspondence: [email protected] (S.C.); [email protected] (D.Y.); Tel.: +86-20-3933-2990 (S.C.); +86-20-8386-2543 (D.Y.) Received: 14 May 2020; Accepted: 4 July 2020; Published: 16 July 2020 Abstract: Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation. Keywords: metabolic reprogramming; drug resistance; reversal of chemoresistance; metabolic regulation; chemoresistance 1. Introduction Chemotherapy and targeted therapy are common methods of tumor treatment, but tumor cells can develop resistance to drugs, leading to the failure of treatment. The development of tumor drug resistance involves general mechanisms and drug-specific or pathway-specific mechanisms (Figure1) [1–3] . Pathway-specific mechanisms require the restoration of the tumor-driving signaling pathway. General mechanisms, common to many drugs, usually involve several aspects. First, the acquisition of resistance is often related to the failure of drug delivery. Multidrug resistance is mediated by the activation of ATP-binding cassette (ABC) transporters. The multidrug resistance protein 1 (MDR1) or P-glycoprotein is one of the members of ABC transporter family. The up-regulation of these proteins, especially MDR1, contributes to the acquired resistance to cytotoxic and targeted drugs. Drug escape can be rendered by cancer stem cells (CSCs). CSCs are a small population of tumor initiating cells Metabolites 2020, 10, 289; doi:10.3390/metabo10070289 www.mdpi.com/journal/metabolites Metabolites 2020, 10, x FOR PEER REVIEW 2 of 14 Metabolites 2020, 10, 289 2 of 15 proteins, especially MDR1, contributes to the acquired resistance to cytotoxic and targeted drugs. Drug escape can be rendered by cancer stem cells (CSCs). CSCs are a small population of tumor thatinitiating exist incells tumors that andexist are in abletumors to survive and are therapeutic able to survive intervention. therapeutic The abilityintervention. of CSCs The resistance ability toof chemotherapyCSCs resistance attributes to chem tootherapy their low at proliferationtributes to th rates,eir low up-regulation proliferation of ABCrates, transporter up-regulation activity of ABC and DNAtransporter repair activity capacity, and and DNA down-regulation repair capacity, and of apoptosis. down-regulation Epithelial-mesenchymal of apoptosis. Epithelial transition-mesenchymal (EMT) alsotransition contributes (EMT) to also the contributes development to ofthe drug development resistance. of EMT drug is resistance. a transdiff EMTerentiation is a transdifferentiati process in whichon epithelialprocess in cellswhich lose epithelial their essential cells lose distinguishing their essential characteristics distinguishing and characteristics acquire instead and acquire mesenchymal instead features.mesenchymal Cells thatfeatures. undergo Cells EMT that can undergo produce EMT a CSC-like can produce phenotype, a CSC leading-like phenotype, to the resistance leading to tumorto the therapy.resistance As to mosttumor cancer therapy drugs. As most eradicate cancer tumor drugs cellseradicate by inducing tumor cells apoptosis, by inducing the apop down-regulationtosis, the down of- cellregulation death pathwaysof cell death is anotherpathways mechanism is another mechanism of drug resistance. of drug resistance. Figure 1. Figure 1. Mechanisms of acquired tumor drug resistance.resistance. Some Some of the reasons for acquired drugdrug resistance are common to many drugs, and others may be drug-specific or pathway-specific. They are resistance are common to many drugs, and others may be drug-specific or pathway-specific. They are all related to the expression and function of specific genes. The pathway-specific mechanisms usually all related to the expression and function of specific genes. The pathway-specific mechanisms usually involve the restoration of the tumor-driving signaling pathway. involve the restoration of the tumor-driving signaling pathway. Metabolic reprogramming, metabolic alterations occurring in tumor cells, is one of the hallmarks of Metabolic reprogramming, metabolic alterations occurring in tumor cells, is one of the hallmarks tumors [4]. Enhancement of cell proliferation in tumors requires metabolic reprogramming, which leads of tumors [4]. Enhancement of cell proliferation in tumors requires metabolic reprogramming, which to the changes of metabolic pathways to generate enough ATP and intermediates for macromolecular leads to the changes of metabolic pathways to generate enough ATP and intermediates for biosynthesis under stress to meet the needs of rapid cell division. It is believed that metabolic macromolecular biosynthesis under stress to meet the needs of rapid cell division. It is believed that reprogramming of tumor cells is the consequence of metabolic adaptation, which involves mutations metabolic reprogramming of tumor cells is the consequence of metabolic adaptation, which involves in oncogenes, consequently dysregulating the expression and activity of some metabolic enzymes mutations in oncogenes, consequently dysregulating the expression and activity of some metabolic and the flux of metabolic pathways, and finally affecting whole cellular metabolism. Changes in enzymes and the flux of metabolic pathways, and finally affecting whole cellular metabolism. Changes in cellular metabolism not only promote tumor development [5–9], but also contribute to cell resistance cellular metabolism not only promote tumor development [5–9], but also contribute to cell resistance to to chemotherapeutics [10–13]. These changes may result from the metabolic adaptation of tumor chemotherapeutics [10–13]. These changes may result from the metabolic adaptation of tumor cells to cells to pharmacological stress, which include adaptations in oxidative stress, lipid metabolism, pharmacological stress, which include adaptations in oxidative stress, lipid metabolism, and bioenergetics; and bioenergetics; dependence on glucose and glycolysis; and an increase in polyamine production, dependence on glucose and glycolysis; and an increase in polyamine production, etc. [14–17]. Although etc. [14–17]. Although the underlying mechanism of metabolic adaptation for drug resistant cells has the underlying mechanism of metabolic adaptation for drug resistant cells has not been well understood, not been well understood, emerging evidences suggest that expression of some metabolic genes or emerging evidences suggest that expression of some metabolic genes or some signal pathways in the drug some signal pathways in the drug resistant cells are deregulated [18–20]. This leads to an increase resistant cells are deregulated [18–20]. This leads to an increase in the uptake of glucose and glutamine by in the uptake of glucose and glutamine by drug resistant cells [21,22]; activation of pathways such drug resistant cells [21,22]; activation of pathways such as glutaminolysis, glycolysis, and fatty acid as glutaminolysis, glycolysis, and fatty acid oxidation [18,23,24]; and promotion of antioxidant oxidation [18,23,24]; and promotion of antioxidant production [22,25] as well as metabolic reprogramming production [22,25] as well as metabolic reprogramming in mitochondria [20]. in mitochondria [20]. The study on the effect of cell metabolism on tumor survival and growth revealed that tumor The study on the effect of cell metabolism on tumor survival and growth revealed that tumor cells are more sensitive to nutrient deprivation and more dependent on some metabolites. Fasting or cells are more sensitive to nutrient deprivation and more dependent on some metabolites.
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