Cancer Letters xxx (2014) xxx–xxx

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Metabolic adaptation to cancer growth: From the cell to the organism Xavier Escoté ⇑, Lluís Fajas ⇑ Department of Physiology, Université de Lausanne, Lausanne, Switzerland

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Article history: Received 30 January 2014 Received in revised form 20 March 2014 Accepted 28 March 2014 Available online xxxx Keywords: Cell cycle Metabolism Glycolysis Cdk4 E2F1 transcription factor Glucose

a b s t r a c t Tumour cells proliferate much faster than normal cells; nearly all anticancer treatments are toxic to both cell types, limiting their efficacy. The altered metabolism resulting from cellular transformation and cancer progression supports cellular proliferation and survival, but leaves cancer cells dependent on a continuous supply of energy and nutrients. Hence, many metabolic enzymes have become targets for new cancer therapies. In addition to its well-described roles in cell-cycle progression and cancer, the cyclin/ CDK–pRB–E2F1 pathway contributes to lipid synthesis, glucose production, insulin secretion, and glycolytic metabolism, with strong effects on overall metabolism. Notably, these cell-cycle regulators trigger the adaptive ‘‘metabolic switch’’ that underlies proliferation. Ó 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Cyclins, cyclin-dependent kinases (CDKs), retinoblastoma proteins (pRBs), and the transcription factors E2F are the core regulators of cellular growth and proliferation, sensing external signals that require precise metabolic responses. Cell-cycle progression has been intensively studied in recent years. The cell cycle is divided into four major phases: G0/G1, S, G2, and M; every transition between phases is strongly regulated. Transition from G0/G1 to S is tightly regulated and depends on the activation of the G1 cyclins/CDKs and the pRB–E2F pathway. CDKs are kinases that phosphorylate serine or threonine residues of their targets in a cell cycle-specific manner. To be active, CDKs must be complexed with cyclins, with the complex functioning as a holoenzyme; cyclins select the specific targets for phosphorylation. Additionally, the activity of cyclin/CDK complexes is determined by the presence or absence of two families of CDK inhibitors (CKIs). The first family includes the inhibitors of Cdk4 (INK4) proteins, which specifically bind and inhibit the catalytic subunits of Cdk4 and Cdk6. The INK4 family includes p16, p15, p18, p19, and p19ARF. The Cip/Kip family, including p21, p27, and p57, is the second family of CKIs. These proteins exhibit broad inhibitory function, including inhibition of the activities of the cyclins and CDKs. Active cyclin/CDK hyperphosphorylates the pRBs, ⇑ Corresponding authors. Address: Department of Physiology, Université de Lausanne, Rue Bugnon 7, 1005 Lausanne, Switzerland. Tel.: +41 216925554. E-mail addresses: [email protected] (X. Escoté), [email protected] (L. Fajas).

mediating the release of the E2F transcription factor and the subsequent expression of several genes involved in cell-cycle progression, apoptosis, and DNA synthesis [6]. In this scenario, cells are able to progress to the next phase of the cell cycle [57]. E2Fs modulate the transcription of several genes through heterodimerization with DP-1 and DP-2 [20], activating the transcription of E2F-responsive genes. Nevertheless, in the presence of a larger complex of unphosphorylated members of the retinoblastoma protein family pRBs (RB1, p107 and, p130), the transcription of these genes is repressed. E2F activity is frequently increased in several human cancers, contributing to the uncontrolled proliferation of cancer cells [13]. Here we review the role of the cyclin/CDK–pRB–E2F axis as a master regulator of the metabolic adaptive response triggered by growth factors. We also consider how cancer cells switch their metabolism, as well as the molecular mechanisms implicated in this process. 2. The ‘‘metabolic switch’’ An adapted ‘‘metabolic switch’’ accompanies most physiological and pathological changes in cellular functions. A fine-tuned and regulated cascade of molecular events senses changes in the environmental conditions of the cell and delivers a proper and specific response via the metabolic pathways of the cell. In this way, metabolism is adapted to the necessities of the cell; intermediary metabolism must be coupled to either biosynthetic or oxidative metabolism.

http://dx.doi.org/10.1016/j.canlet.2014.03.034 0304-3835/Ó 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: X. Escoté, L. Fajas, Metabolic adaptation to cancer growth: From the cell to the organism, Cancer Lett. (2014), http:// dx.doi.org/10.1016/j.canlet.2014.03.034

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For tumour progression, cancer cells undergo high rates of biosynthesis of lipids and other macromolecules to construct new cells [37,77]. Large amounts of energy are required to carry out these processes. However, a subset of cancer stem cells has long doubling times, for that reason we will focus in this review in the context of late metastasis. In late-stage cancer, when the mass of the tumour is large, energy consumption becomes quantitatively important. An estimated 17,700 kcal are required over 3 months to support metastatic colorectal cancer. To obtain this large amount of energy, the bulk of cancer cells become highly glycolytic, undergoing non-aerobic fermentation of glucose to lactate. Lactate accumulates inside cancer cells and is exported out of the cells by the monocarboxylate transporter family; the resulting lactic acidosis is quite common in cancer patients [17]. Impaired functioning of the monocarboxylate transporters causes substantial defects in cancer-cell proliferation and tumour growth, indicating that cancer cells depend on efficient lactate secretion. Therefore, cells use glycolysis to obtain most of their energy in the form of ATP, as well as the intermediate metabolites necessary for the biosynthesis of macromolecules. Under aerobic conditions, complete fermentation of glucose to lactate is not the most efficient way to obtain energy. When glycolysis occurs in the presence of oxygen, it is called ‘‘aerobic glycolysis’’ or the ‘‘Warburg effect’’ [79–81]. Warburg suggested that alterations in the metabolism of cancer cells were due mainly to the malfunction of mitochondria. However, this idea of a ‘‘metabolic switch’’ in cancer cells has been reformulated to include the relationships between cancer genes and metabolic alterations. The molecular mechanisms underlying the ‘‘metabolic switch’’ observed in cancer cells are not completely understood. Energy metabolism is therefore gaining attention as an alternative therapeutic target for tumours [51]. Glucose is essential for cancer-cell proliferation, not only because it is the main energy source for the cell, but because glucose may be equally important as a substrate for the pentose phosphate pathway [85], an essential component of the generation of new nucleotides and a source of NADPH equivalents required for the synthesis of fatty acids. Aerobic glycolysis remains the major pathway used by cancer cells. Glycolysis offers several advantages to highly proliferating cancer cells: (1) It enables use of the most abundant extracellular source of energy, glucose, and (2) glycolysis-derived ATP production can exceed that obtained during oxidative phosphorylation.

3. The cancer-host metabolic dependance Data about diet are not consistent between in vitro and in vivo experiments. In this way, glucose deprivation induces oxidative stress and cytotoxicity in cancer cells, which indicates a positive role of diet fighting against proliferation [71]. Nevertheless, this fact presents a limited action in vivo and sometimes with contradictory results because subjected animal models to a low-carbohydrate diet exhibited just a reduced inhibition of tumour growth [18]; but on other studies, diet significantly prolonged the survival of a mouse prostate cancer xenograft model [48]. With a nutritionally balanced diet low in carbohydrates and high in fat, human patients experienced long-term tumour management [54,64]. Therefore, use of this restricted diet partially controls glucose levels in the organism, reducing the rapid proliferation of cancer cells via a decrease in glycolysis rates and in the availability of intermediate metabolites for macromolecule synthesis. Unfortunately, this treatment is not sufficient for cancer therapy for several reasons. First, a chronically restricted diet is expected to delay but not to stop the progression of the disease [11,52,66], and this delay may only occur for some cancers types [34]. Second, moderate diet restriction produces a long-term loss of body weight caused by

the loss of adipose tissue and muscle cachexia, which may be tolerated by only a small percentage of cancer patients [74] [25] [24,61]. Third, long-term dietary restriction was accompanied by delayed wound healing and immunological impairment in in vivo studies [35,62]. Thus, in addition to controlling dietary glucose, treatment could also target liver gluconeogenesis, which is an important secondary source that can generate significant amounts of glucose from glycerol, glucogenic amino acids, or lactate, as is the case for cancer cachexia [32]. The best diagnostic sign of cancer cachexia is involuntary weight loss [5]. Cancer cachexia could be considered to be an initial adaptive response for accessing body stores of energy and protein [72]. Cachexia is clinically obvious in its advanced phase (gross loss of adipose tissue and skeletal muscle). Cachexia is divided into three phases: precachexia, cachexia, and refractory cachexia. Cancer cachexia therapy focuses on the time of cancer diagnosis because the latter phases are less amenable to reversal [23]. Cancer cachexia is a multifactorial syndrome that is defined by a progressive reduction of skeletal muscle mass (with or without loss of adipose tissue) that cannot be reversed by conventional nutritional support. Cachexia is characterized by a negative energy balance and protein insufficiency, which are driven by a variable combination of reduced food intake and abnormal metabolism [38]. In cancer patients, reduced food intake is caused by primary anorexia. Simultaneous high rates of metabolism and catabolism as well as lower rates of anabolism exacerbate the weight loss and triggering systemic inflammation. Cachexia is thus a combination of dietary and metabolic factors [38,55,67]. Cancer cachexia is a complex syndrome, and can often occur in the presence of malnutrition, agerelated changes in anabolism, physical deconditioning, and comorbidity [19]. The effects of cancer cachexia and the complications after cancer therapy are not easy to differentiate because weight loss can be due to several features of cancer treatment [4,7,8,69]. Mobilization of resources from skeletal muscle and adipose tissue is an appropriate response. Cancer cells alter energy regulation by eliciting an excessive inflammatory response that augments both central and peripherally mediated catabolic events [72]. Cancer therapy is progressively targeted against molecular pathways that are responsible for cellular proliferation, such as the PI3K, AKT, and mTOR pathways; these pathways are involved in the activation of muscle protein anabolism. Consequently, these treatments result in muscle wasting, a significant side effect of drugs that target these pathways [10,27,75]. Unfortunately, cachexia is rarely treated actively, mainly due to a lack of knowledge about clinical nutrition in cancer [70]. However, current progress in cachexia therapy promises to improve the systematic treatment of cachexia. Cachexia is a good model of how cancer cells force the host organism to change metabolism. Another argument to prove that cancer cells takeover the host metabolism is lactate cycle. Lactate secretion is also a hallmark of cancer cells. Lactate is secreted, and since it cannot be fully excreted it is transported to liver cells, where is used as substrate for gluconeogenesis. Tumors may take advantage of this pathway. Lactate is secreted by cancer cells to signal to liver the requirement of glucose by the tumor and facilitates glucose recycling through lactate conversion in liver. This is strikingly similar to the Cory cycle implemented between liver and muscle during acute exercise. We propose that tumor cells customize the metabolism of the whole organism to receive enough glucose. Increased glucose requirement is likely provided by excess glucose production in liver of the host organism. Glucose is also synthesized from other substrates than lactate such as aminoacids, which are also increased during cancer progression. Interestingly some studies from the 60’s already proposed inhibition of gluconeogenesis as a treatment of cancer [28]. Furthermore, increased glucose turnover is typically observed in cancer patients

Please cite this article in press as: X. Escoté, L. Fajas, Metabolic adaptation to cancer growth: From the cell to the organism, Cancer Lett. (2014), http:// dx.doi.org/10.1016/j.canlet.2014.03.034

X. Escoté, L. Fajas / Cancer Letters xxx (2014) xxx–xxx

[45]. Notably, increased hepatic gluconeogenesis was observed in lung, breast, or pancreatic cancer patients [41,42,82]. The mechanisms involved in the cross-talk between tumors and distant normal liver are poorly understood, and the factors that coordinate the gluconeogenic response are not known. There is therefore a need to understand how the tumor takes over the host organism metabolism. 4. Fatty acids in cancer In cancer cells, glucose is also used for anabolic processes such as protein glycosylation, serine synthesis, and ribose production, which are necessary for new DNA strands [15,70,16,30,44,78,84]. The control of these processes by the oncogenes MYC and RAS emphasizes the importance of these pathways in cancer progression. In addition to glucose and glutamine, fatty acids are a critical energy source. They can be incorporated from the extracellular medium, be obtained from hydrolyzed triglycerides via b-oxidation by the action of hydrolases, or be produced by de novo lipid synthesis [68]. Several types of cancer cells undergo exacerbated endogenous de novo fatty-acid synthesis to produce new structural lipids [39,49,59]. In contrast, normal adult cells preferentially use circulating fatty acids. It is likely that one of the most important roles of aerobic glycolysis of cancer cells is to provide metabolic intermediates required for de novo fatty acid synthesis. De novo fatty acid biosynthesis is a hallmark of tumor cells, including liver cancer cells [86]. Increased lipogenesis is reflected in the significantly elevated activity of lipogenic enzymes, such as ATP citrate lyase (CL), which provides acetyl CoA for fatty acid biosynthesis, or the fatty acid synthase (FAS), which catalyzes the condensation of acetyl CoA and malonyl CoA [39]. De novo fatty acid biosynthesis is essential for cancer cells to synthesize new membranes, which have a particular lipidic composition that facilitates the formation of lipid rafts for increased signalling of cell growth receptors. Lipogenesis also participates, in cancer cells, to generate signaling molecules, such as phosphatidyl inositol, phosphatidy serine, or phosphatidy coline, which are important to activate proliferative and survival pathways, notably the AKT pathway. Moreover, some lipid synthesis intermediates, such as malonyl CoA participate in the transcriptional regulation of growth factor receptors. On the other hand, fatty acids are catabolized by b-oxidation. The relevance of b-oxidation to cancer-cell function has not been rigorously examined. Nevertheless, recent studies have begun to highlight a role for this metabolic pathway in cancer, a discovery that is associated with new and exciting therapeutic implications (extensively reviewed by Carracedo et al.) [12]. 5. Cancer and cell-cycle regulators Research over the past several decades has identified many oncogenes (ras, wnt, and AKT), and cell-cycle regulators (such as the Cdk4-E2F1 axis) that are frequently altered in several types of tumours. The majority of these abnormalities are associated with signaling pathways. New and accumulating evidence connects signaling pathways directly to the control of cellular metabolism, growth and proliferation through the regulation of metabolic enzymes. Moreover, some of the key enzymes implicated in this metabolic control are mutated or altered during cancer progression [60]. Cancer cells maintain their high rate of growth through constant activation of growth signaling pathways and inactivation of tumour suppressors. In the context of cancer, signaling pathways such as AKT and mTOR directly reprogram glucose metabolism, allowing greater nutrient uptake and an increase in macromolecular biosynthesis to support cellular proliferation. Activity of these oncogenes results in the inhibition of oxidative

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metabolism and increased glycolysis [26,29,33,46,65,83]. Recently, cancer cells have been shown to express specific isoforms of glycolytic enzymes [60], suggesting the potential to develop isoformspecific inhibitors that increase drug specificity to cancer cells. These targets could include key metabolic enzymes such as the muscle isoforms of hexokinase-2 and phosphofructokinase-2; in cancer cells, expression of these isoforms led to the identification of isoform inhibitors that substantially suppressed tumour growth in preclinical studies [47,73]. It is intuitive to hypothesize that a single signaling pathway connects cellular functions with a proper metabolic response. Consistent with this line of thinking, cell-cycle regulators, particularly the cyclin/Cdk4–pRB–E2F1 axis, are critical factors that control cellular proliferation. It is therefore not surprising that they are also key factors in metabolic control. In general, proliferation leads to a strong demand for glucose for the biosynthesis of new structures for the new cells. Glucose is not only the main source of energy, but is also the source of redox equivalents that are normally created by anaerobic glycolysis and anabolic processes such as protein or lipid biosynthesis. Thus, as stated above, one of the main functions of glycolysis is to provide intermediates for the biosynthesis of macromolecules that support the indispensable proliferation phenotype of cancer cells, indicating that a direct connection between metabolic regulation and the regulation of cell-cycle progression should also be expected. There is increasing evidence to prove that the cyclin/Cdk4–E2F1– pRB axis exerts specific effects on metabolism. In addition, we previously demonstrated that the E2F transcription factors modulate differentiation from preadipocytes to mature adipocytes by regulating the expression of the principal regulator of adipogenesis PPARc [22]; pRB represses the transcription factor PPARc through the recruitment of HDAC3 [21]. Similarly, we also confirmed that other members of the cyclin/Cdk4–E2F1–pRB axis play an important role in adipocyte development [1,31,63]. The principal phenotypes presented by mice deficient for members of the cyclin/Cdk4– E2F1–pRB axis are metabolic. Similarly, mice deficient for Cdk4 or E2F1 exhibited deep metabolic changes due to altered glucose homeostasis and compromised mitochondrial function; this phenotype was completely reversed in mice harbouring a highly active Cdk4 allele [2]. The participation of genes encoding CKIs in metabolic pathways is consistent with metabolic regulation by members of the cyclin/ Cdk4–E2F1–pRB axis. Disruption of the CKIs p18 and p27 promotes growth of mice [36,40]. These results are in accordance with inhibition by Cdk4, since Cdk4-deficient mice are smaller than their wild-type counterparts. Moreover, p27 and p21 double-knockout mice display important global metabolic adaptations that affect adipocytes and induce hypercholesterolaemia, glucose intolerance, and insulin insensitivity, which are characteristics of an obesity profile [53]. Interestingly, these changes are a critical step of the ‘‘metabolic switch’’ observed in cancer cells. These factors support cell-cycle progression in some cell types, whereas the same factors generate a metabolic response in other cells. Interestingly, Cdk4 is activated by insulin in pancreatic b-cells. In this cell type, the cyclin/Cdk4– E2F1–pRB axis functions as a sensor of the nutritional and energetic status of the cell, enabling insulin secretion [3] and repressing mitochondrial oxidative metabolism energy expenditure [9]. Metabolic regulation by the cyclin/Cdk4–E2F1–pRB axis is not restricted to the control of pancreatic b-cells. Diet-induced obesity is avoided in cyclin D3-deficient mice, which are sensitive to insulin and exhibit a reduced adipocyte size [63]. Cyclin D3 directly interacts with the master regulator of adipogenesis PPARc, reducing adipose tissue mass. Additionally some polymorphisms in the gene encoding Cdk4 contribute to type II diabetes-associated obesity [50].

Please cite this article in press as: X. Escoté, L. Fajas, Metabolic adaptation to cancer growth: From the cell to the organism, Cancer Lett. (2014), http:// dx.doi.org/10.1016/j.canlet.2014.03.034

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Cdk5, a kinase that also belongs to the Cdk family, likewise regulates metabolism. In pancreatic b-cells, glucose and insulin activate Cdk5 [43,76], which also regulates insulin secretion in these cells. In adipocytes, Cdk5 modulates the expression of some adipokines, including adiponectin, leptin, and adipsin [14,56]. A common polymorphism in the Cdk5 regulatory unit has been associated with the development of type II diabetes [58]. Taken together, all these lines of evidence corroborate the hypothesis of reciprocal regulation between cell-cycle regulators and metabolic processes. This regulation seems not to be limited to a single pathway, but is a general and common mechanism of dual regulatory pathways. 6. Conclusions and perspectives Cancer cells display numerous layers of metabolic alterations that affect cellular proliferation via the deregulation of oncogenic pathways and tumour suppressors. Increasing evidence indicates that cancer-cell metabolism is reprogrammed through the regulation of metabolic enzymes by various cell-cycle regulators. Cancer metabolism can thus be perceived as a network of pathways with plasticity, feedback loops, and crosstalk that ensure the fitness of tumour cells. Energy is crucial to these processes, and glycolysis may provide some of this plasticity by enabling the production of ATP when required and by generating metabolic intermediates for cellular growth. The ‘‘metabolic switch’’ is governed by cellcycle regulators. The cyclin/Cdk4–E2F1–pRB axis regulates both cellular growth and metabolism, integrating these processes in normal cells and in transformed cancer cells. We have reviewed the most recent studies showing that cell-cycle regulators control metabolic processes such as lipid synthesis and glycolysis, which are involved in the ‘‘metabolic switch’’ necessary for cancer development. This dual regulation of proliferation and metabolism by the cyclin/Cdk4–E2F1–pRB axis is crucial to the viability of cancer cells. A better understanding of these signaling pathways will facilitate the identification of new strategies to treat patients who may benefit from targeted metabolic therapies. Conflict of Interest The authors declare that they have no conflict of interest. Acknowledgements Fajas lab is supported by grants from the SNF and University of Lausanne. The members of the lab are acknowledged for discussions. References [1] A. Abella, P. Dubus, M. Malumbres, S.G. Rane, H. Kiyokawa, A. Sicard, F. Vignon, D. Langin, M. Barbacid, L. Fajas, Cdk4 promotes adipogenesis through PPARgamma activation, Cell Metab. 2 (2005) 239–249. [2] V. Aguilar, L. Fajas, Cycling through metabolism, EMBO Mol. Med. 2 (2010) 338–348. [3] J.S. Annicotte, E. Blanchet, C. Chavey, I. Iankova, S. Costes, S. Assou, J. Teyssier, S. Dalle, C. Sardet, L. Fajas, The CDK4–pRB–E2F1 pathway controls insulin secretion, Nat. Cell Biol. 11 (2009) 1017–1023. [4] S. Antoun, L. Birdsell, M.B. Sawyer, P. Venner, B. Escudier, V.E. Baracos, Association of skeletal muscle wasting with treatment with sorafenib in patients with advanced renal cell carcinoma: results from a placebo-controlled study, J. Clin. Oncol.: Official J. Am. Soc. Clin. Oncol. 28 (2010) 1054–1060. [5] J. Arends, G. Bodoky, F. Bozzetti, K. Fearon, M. Muscaritoli, G. Selga, M.A. van Bokhorst-de van der Schueren, M. von Meyenfeldt, Dgem, G. Zurcher, R. Fietkau, E. Aulbert, B. Frick, M. Holm, M. Kneba, H.J. Mestrom, A. Zander, Espen, ESPEN guidelines on enteral nutrition: non-surgical oncology, Clin. Nutr. 25 (2006) 245–259. [6] C. Attwooll, E. Lazzerini Denchi, K. Helin, The E2F family: specific functions and overlapping interests, EMBO J. 23 (2004) 4709–4716.

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Please cite this article in press as: X. Escoté, L. Fajas, Metabolic adaptation to cancer growth: From the cell to the organism, Cancer Lett. (2014), http:// dx.doi.org/10.1016/j.canlet.2014.03.034