Biochimie 0 SociW

(1992)

fraqaise

74.959-974

959

de biochimie et biologie moleculaire / Elsevier, Paris

Review

Deviant energetic metabolism of glycolytic cancer cells LG Baggetto* LBTMSI.

UMR

24 CNRS, 43 Bd du II Novembre 1918,69622

Villeurbanne

Cedex. France

(Received 19 March 1992; accepted 4 Sune 1992)

SuFmary -, The central glycolytic and oxidative pathways and the ATP-producing mechanisms differ in sane and malignant cells by their regulation and dynamics. Fist-growing, poorly-differentiated cancer cells characteristically show high aerobic glycolysis. In the same way, cholesterol biosynthesis, which occurs by normal pathways in tumors, is deficient in feed-back regulation and in steroltransportmechanisms. Other metabolic ways are deficient, as for example, intramitochondrial aldehyde catabolism, at the origin of a possible acetaldehyde toxicity, which can be circumvented by the synthesis of an unusual and neutral product for mammalian cells acetoin, through tumoralpyruvate dehydrogenase.If most of the glycolytic pyruvate is deviated to lactate production, little of the remaining carbons enter a truncated Krebs cycle where citrate is preferentially extruded to the cytosol where it feeds sterol synthesis. Glutamine is the major oxidizable substrate by tumor cells. Inside the mitochondrion, it is deaminated to glutamate through a phosphate-dependent glutaminase. Glutamate is then preferentially transaminated to a-ketoglutarate that enters the Krebs cycle. Glutamine may be completely oxidized through the abnormal Krebs cycle only if a way of forming acetyl CoA is present: cytosolic malate entering mitochondria is preferentially oxidized to pyruvate + CO2 through an intrrumitochondrial NAD(P)+ -malic enzyme, whereas intramitochondrial malate is preferentially oxidized to oxaloacetate through malate dehydrogenase, thus providing a high level of intramitochondrial substrate compartmentation. These and other regulatory aberrations in tumor cells appear to be reflections of a complex set of non-random phenotypic changes, initiated by expression of oncogenes. cancer cells I glycolysis / metabolism

Introduction The study of energetic metabolism of cancer cells has

evolved in successive waves. Many data have been collected since Warburg discovered in 1926 that cancer cells had a respiratory deficiency that played an important role in carcinogenesis [ 11.These data led to the discovery and understanding of a highly deviated general metabolism that transformed cells into energy-dissipating entities. These cells are able to develop several parades such as ectopic isozymes to face the obstacles they create or encounter. The studies that followed were naturally oriented to the genes that may be responsible for the cancer phenotype. Cellular and viral oncogenes have thus been discovered followed by the recent discovery of anti-oncogenes and co-oncogenes that participate in the different steps *Present address: Laboratoire FonctioMelle, IBCP-UPR 412

de Biochimi8e Structurale et CNRS, Passiage du Vercors,

69007 Lyon, France. Acetyl CoA, acetyl coenzyme A; AIDH, aldehyde dehydrogenase; CK, creatine kinase; Co~4, coenzyme A; HDL, high density lipoprotein, PEP, phosphoenol pyruvate; PDH, pymvate dehydrogenase complex.

Abbreviations:

of carcinogenesis. During these ‘genetic’ years, mitochondria of tumor cells have been deserted. It was only in the 1970s that Hadler er al [2] hypothesized the possible relationship linking carcinogenesis and mitochondria. Cancer cells present a variety of differentiation states spanning from the highly differentiated cell, close to the original parental cell, with a normal glycolysis and a slow growth rate, to the highly de-differentiated, highly glycolytic cell with a rapid growth rate. Their analysis allowed us to understand the strict compartmentation that characterizes their cytoplasm and their organelles, with some aspects of the fine, complex and many regulations that govern division, differentiation and programmed cell death. The diverse and multiple metabolic deviations resulting from the cancer state progress with the advancement of the cancer phenotype as proto-oncogenes get activated to drive the initial sane cell to immortalization and metastasis. To survive, cancer cells will kill neighboring cells, leaning on an abnormal, expensive metabolism, but somehow equilibrated since it is compatible with the existence of these parasites of the living organisms.

960 Central metabolic pathways are recalled in figures 1 and 2. The major characteristic of fast growing tumor cells is their elevated rate of glycolysis (fig 3). This metabolic pathway contains a different isozymic composition from the sane cell; the activity of key enzymes of regulation is often increased. These changes correlate with the malignant transformation and with the progression of malignancy [3]. A major consequence of such a high glycolysis is that glucose carbons are no longer the major carbon source for respiration; glutamine plays this role and enters an abnormal, truncated, Krebs cycle. However, glutamine may be completely oxidized through such a cycle only if a progression-linked enzyme such as NAD(P)+ malic enzyme furnishes acetyl-CoA units to feed the Krebs cycle (in many glycolytic cancer cells, lipidderived acetyl CoA is not preponderant). Actually, as little as 10% of the glycolytic pyruvate give acetyl,+A through a pyruvate dehydrogenase complex (PDH) whose function diverges from that of normal cells: one new and recent discovery concerns the procluction of acetoin from an elevated non-oxidative decarboxylation of pyruvate by tumoral PDH, at the origin of an original new metabolic pathway in glycolytic cancer cells. This unusual way in mammalian cells is probably dictated by the needs for acetaldehyde detoxification, which can no longer be the fact in mitochondrial aldehyde dehydrogenases, the latter being absent in cancer cells. The purpose of this review is to focus on deviations

of energetic metabolism of cancer cells and to propose several mechanisms that control their high glycolysis rate. Mechanisms controlling the glycolysis rate in rapidly growing cancer cells

According to a generally admitted postulate, ADP and Pi produced by the plasma membrane Na+/K+ ATPase activity are feedback signals for the control of oxidative energetic metabolism [4]. In normal tissues and in slowly growing tumors, the ADP/Pi pool is more sol-

icited by mitochondrial reactions than by glycolysis. In these cells, an efficient mechanism must couple the Na+/K+ATPase activity to the level of mitochondrial ATP generation. Such a mechanism may be schematized according to the work of several authors [S-8]: ADP and ATP are largely compartmentalized in the location of ATP regeneration and utilization (the sum

of adenine nucleotides in the cell remains constant). These microcompartments are constituted by the proteic complexes located at the plasma membrane level, between Na+/K+ATPase and creatine kinase (CK), on the one hand, and between adenine nucleotide translocase and creatine kinase, on the other. These proteic groups would work as integrated units of catalytic activity. The cyclic passage of ATP and ADP through the catalytic centers of Na+/K* ATPase and creatine kinase produces a chemical potential of ADP and ATP that is favorable to maximal kinetic and thermodynamic Na+/K+ATPase efficiency [9]. Control of respiration uses a shuttle mechanism in which creatine and ADP are the signals for a negative feedback mechanism. The coordinated action of adenine nucleotide translocase and creatine kinase favorably changes the chemical potential of ADP and ATP in the active centers of creatine kinase to orient the reaction in the direction of phosphocreatine synthesis. CK is present under different isoforms: MM, the muscle type, BB, found in heart, brain and fetal muscle, MB, found in muscle and heart, and CKm, found in muscle, heart and brain mitochondria. It has been postulated that the creatine kinase form that is associated with Na+/K+ATPase is an MM isozyme [8] (an isofortn that is rather specific for differentiated sarcomeric muscle) necessary for the formation of such proteic groups. However, another isoform of a fetal type has been discovered in several human tumors [lo], in rat hepatomas and in mouse ascitic tumors [ 111;this form is of the BB type (the form that is found in brain and in some other tissues) and cannot be organized in proteic groups with the proteins mentioned above. To date it is not possible to assess that creatine kinase of tumor cells may participate in the ‘creatine/phosphocreatine shuttle’: for this to occur, both mitochondrial and cytosolic creatine kinase

Fig 1. Glycolysis and gluconeogenesis. The left side of the figure represents the glycolytic pathway. It is called anaerobic when the glucose oxidation process leads to the formation of lactate. Conversely, it is called aerobic when the degradation of glucose leads to pyruvate that will be oxidized in the Krebs cycle. Glycolysis is composed of two phases: the first one concerns glucose phosphorylation and its conversion into glyceraldehyde-3-phosphate. The second one concerns the conversion of glyceraldehyde-3-phosphate into pyruvate (or lactate) coupled to ATP formation. Enzymes that control the metabolic flux (or key enzymes) are represented with their international classification number on a black frame. Glucosed-phosphate exerts a negative regulation on hexokinase whereas ATP and citrate inhibit phosphofructokinase, which is inhibited by AMP Fatty acids and acetyl CoA inhibit pyruvate kinase. The right side of the figure represents gluconeogenesis. This pathway is controlled at the levels of the indicated major locations. Formation of phosphoenolpyruvate involves mitochondria, in particular for the transfomation of pyruvate into oxaloacetate. P stands for the phosphate group.

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Deviant energetic metabolism of glycolytic cancer cells.

The central glycolytic and oxidative pathways and the ATP-producing mechanisms differ in sane and malignant cells by their regulation and dynamics. Fa...
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