Title: Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism
Abstract: Metabolic reprogramming has emerged as a hallmark of cancer. MicroRNAs are noncoding RNAs that posttranscriptionally repress the expression of target mRNAs implicated in multiple physiological processes, including apoptosis, differentiation, and cancer. MicroRNAs can affect entire biological pathways, making them good candidates for therapeutic intervention compared with classical single target approaches. Moreover, microRNAs may become more relevant in the fine-tuning adaptation to stress situations, such as oncogenic events, hypoxia, nutrient deprivation, and oxidative stress. Furthermore, artificial microRNAs can be designed to modulate the expression of multiple targets of a specific pathway. In this review, we describe the metabolic reprogramming associated to cancer, with a special interest in the altered lipid metabolism. Next, we describe specific features of microRNAs that make them relevant to target cancer cell metabolism. Finally, in an attempt to open new therapeutic windows, we emphasize two exciting scenarios for microRNA-mediated intervention that need to be further explored: 1) the cooperation between FA biosynthesis (lipogenesis) and FA oxidation as complementary partners for the survival of cancer cells; and 2) the regulation of the intracellular lipid content modulating both lipid storage into lipid droplets, and lipid mobilization through lipolysis and/or lipophagy. Metabolic reprogramming has emerged as a hallmark of cancer. MicroRNAs are noncoding RNAs that posttranscriptionally repress the expression of target mRNAs implicated in multiple physiological processes, including apoptosis, differentiation, and cancer. MicroRNAs can affect entire biological pathways, making them good candidates for therapeutic intervention compared with classical single target approaches. Moreover, microRNAs may become more relevant in the fine-tuning adaptation to stress situations, such as oncogenic events, hypoxia, nutrient deprivation, and oxidative stress. Furthermore, artificial microRNAs can be designed to modulate the expression of multiple targets of a specific pathway. In this review, we describe the metabolic reprogramming associated to cancer, with a special interest in the altered lipid metabolism. Next, we describe specific features of microRNAs that make them relevant to target cancer cell metabolism. Finally, in an attempt to open new therapeutic windows, we emphasize two exciting scenarios for microRNA-mediated intervention that need to be further explored: 1) the cooperation between FA biosynthesis (lipogenesis) and FA oxidation as complementary partners for the survival of cancer cells; and 2) the regulation of the intracellular lipid content modulating both lipid storage into lipid droplets, and lipid mobilization through lipolysis and/or lipophagy. A hallmark of cancer is the metabolic reprogramming to sustain cell proliferation and metastasis (1.Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (32291) Google Scholar). Regardless of the oncogenic or tumor suppressor event implicated, cancer cells rely on a positive balance of energy and biosynthetic requirements. Moreover, cancer metabolism is the result of a combination of cell-autonomous genetic alterations and flexibility to adapt to the microenvironment (oxygen, pH, and nutrient availability) (2.Parks S.K. Chiche J. Pouyssegur J. pH control mechanisms of tumor survival and growth.J. Cell. Physiol. 2011; 226: 299-308Crossref PubMed Scopus (239) Google Scholar, 3.Le A. Lane A.N. Hamaker M. Bose S. Gouw A. Barbi J. Tsukamoto T. Rojas C.J. Slusher B.S. Zhang H. et al.Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.Cell Metab. 2012; 15: 110-121Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 4.Chen J.Q. Russo J. Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells.Biochim. Biophys. Acta. 2012; 1826: 370-384PubMed Google Scholar). MicroRNAs are small single-stranded noncoding RNAs (19–25 nucleotides) that posttranscriptionally repress the expression of mRNAs implicated in nearly all cellular processes, such as cell cycle, apoptosis, autophagy, stemness, differentiation, angiogenesis, inflammation, drug resistance, stress response, transformation, and migration. MicroRNAs are frequently deregulated in cancer and so they are important biomarkers for diagnosis and prognosis of the cellular outcome (5.Kosaka N. Iguchi H. Ochiya T. 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Virol. 2013; 85: 1523-1533Crossref PubMed Scopus (9) Google Scholar), and this makes them good candidates for therapeutic intervention compared with classical single target approaches. In this review, we briefly describe the altered cancer cell metabolism, and then we discuss the use of microRNAs as modulators of specific metabolic pathways in cancer (summarized in Fig. 1). We note the promising potentiallity of microRNAs for therapeutic intervention toward the altered lipid metabolism in cancer (summarized in Fig. 2). In an attempt to open new therapeutic windows, we emphasize two exciting scenarios for microRNA-mediated intervention that need to be further explored: 1) the cooperation between FA biosynthesis (lipogenesis) and FA oxidation (FAO) as a survival mechanism in cancer; and 2) the regulation of the intracellular lipid content in the cross-talk between lipid storage into lipid droplets (LDs) and lipid mobilization by lipolysis and/or lipophagy (Table 1).Fig. 2Summary of the lipid metabolism pathways that are described in this review: Lipogenesis and FAO can cooperate as partners to increase plasticity of cancer cells. De novo FA and cholesterol biosynthetic pathways and LD formation are indicated by the orange arrows. FAO contributes to increase survival under energy and oxidative stress (indicated by blue arrows). Intracellular lipid content is the result of a dynamic balance between neutral lipid storage in LDs (TAG and CE) and lipid mobilization by neutral lipases (lipolysis) or acidic lipases (lipophagy) that release FFA for FAO in mitochondria or substrates for lipid-related signaling molecules, as well as structural molecules for membrane biosynthesis. In addition, LDs contain an enriched proteome that regulates lipid mobilization and protects from toxic unfolded proteins, buffers excess of proteins, and regulates lipid mobilization when required. Lipophagy is an active process for lipid mobilization that contributes to increase the survival and fitness of cancer cells. Orange arrows, FA and lipid biosynthesis; blue arrows, lipid mobilization and FAO; green boxes, enzymes implicated in lipid biosynthesis; purple boxes, enzymes implicated in lipid mobilization [lipases (adipose TAG lipase, HSL, MAGL) and phospholipases (PLA1, PLA2, PLA3) are indicated in purple]. Lipophagy-related acidic lipases are indicated in yellow. mit, mitochondria; G3P, glycerol-3-phosphate; MAG, monoacylglycerol; CE, cholesterol esters.; PG, phosphatidylglycerol; PS, phosphatidylserine; PC, phosphatidylcholine, PE, phosphatidylethanolamine; PI, phosphatidylinositol; Cho, choline; CPT1A2, carnitine palmitoyltransferase 1A2; CD36, thrombospondin receptor; FATP, fatty acid transport protein.View Large Image Figure ViewerDownload Hi-res image Download (PPT)TABLE 1Summary of the microRNAs cited and their targetsMicroRNATargetReferenceMicroRNA-195-5pGLUT3(87.Fei X. Qi M. Wu B. Song Y. Wang Y. Li T. MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression.FEBS Lett. 2012; 586: 392-397Crossref PubMed Scopus (75) Google Scholar)MicroRNA-223GLUT4(88.Laios A. O'Toole S. Flavin R. Martin C. Kelly L. Ring M. Finn S.P. Barrett C. Loda M. 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Cancer cells alter their metabolism to provide the additional energy and anabolic demands of biosynthesis (nucleotides, lipids, proteins) that sustain cell proliferation and metastasis. Although proliferative metabolism is a hallmark of cancer, it is important to note that there is incredible biological diversity across cancer types and even heterogeneities within a single tumor. This affects not only the mechanism by which the metabolic reprogramming is achieved, but also the specific set of metabolic dependencies. For example, the exogenous glutamine dependency varies across different breast tumor subtypes (9.Kung H.N. Marks J.R. Chi J.T. Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia.PLoS Genet. 2011; 7: e1002229Crossref PubMed Scopus (158) Google Scholar). In addition, cancer cells present increased metabolic plasticity that allows them to continuously adapt to changes in microenvironment. 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This indicates that the altered tumor metabolism is the result of a combination of cell autonomous genetic alterations and flexibility to adapt to microenvironment changes (oxygenation, pH, and nutrient availability) (2.Parks S.K. Chiche J. Pouyssegur J. pH control mechanisms of tumor survival and growth.J. Cell. Physiol. 2011; 226: 299-308Crossref PubMed Scopus (239) Google Scholar, 3.Le A. Lane A.N. Hamaker M. Bose S. Gouw A. Barbi J. Tsukamoto T. Rojas C.J. Slusher B.S. Zhang H. et al.Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells.Cell Metab. 2012; 15: 110-121Abstract Full Text Full Text PDF PubMed Scopus (603) Google Scholar, 4.Chen J.Q. Russo J. Dysregulation of glucose transport, glycolysis, TCA cycle and glutaminolysis by oncogenes and tumor suppressors in cancer cells.Biochim. Biophys. Acta. 2012; 1826: 370-384PubMed Google Scholar). The most prominent metabolic alteration in cancer proliferating cells is the increased glucose uptake and the use of aerobic glycolysis versus mitochondrial respiration regardless of the abundance of oxygen (Warburg effect) (1.Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144: 646-674Abstract Full Text Full Text PDF PubMed Scopus (32291) Google Scholar, 12.Warburg O. Geissler A.W. Lorenz S. On growth of cancer cells in media in which glucose is replaced by galactose [Article in German].Hoppe Seylers Z. Physiol. Chem. 1967; 348: 1686-1687Crossref PubMed Google Scholar). In spite of the lower energy generated by aerobic glycolysis, this metabolic preference sustains intermediates for biosynthesis of lipids, nucleotides, and amino acids, which are required to sustain cell proliferation. To compensate the low efficiency of ATP production compared with mitochondrial respiration, cancer cells upregulate glucose transporters (13.Macheda M.L. Rogers S. 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