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Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells

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Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells International Journal of Molecular Sciences Review Unappreciated Role of LDHA and LDHB to Control Apoptosis and Autophagy in Tumor Cells Kaja Urba ´nska 1 and Arkadiusz Orzechowski 2,* 1 Department of Morphological Sciences, Warsaw University of Life Sciences—SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland; [email protected] 2 Department of Physiological Sciences, Warsaw University of Life Sciences—SGGW, Nowoursynowska 159, 02-776 Warsaw, Poland * Correspondence: [email protected] Received: 26 March 2019; Accepted: 24 April 2019; Published: 27 April 2019 Abstract: Tumor cells possess a high metabolic plasticity, which drives them to switch on the anaerobic glycolysis and lactate production when challenged by hypoxia. Among the enzymes mediating this plasticity through bidirectional conversion of pyruvate and lactate, the lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB), are indicated. LDHA has a higher affinity for pyruvate, preferentially converting pyruvate to lactate, and NADH to NAD+ in anaerobic conditions, whereas LDHB possess a higher affinity for lactate, preferentially converting lactate to pyruvate, and NAD+ to NADH, when oxygen is abundant. Apart from the undisputed role of LDHA and LDHB in tumor cell metabolism and adaptation to unfavorable environmental or cellular conditions, these enzymes participate in the regulation of cell death. This review presents the latest progress made in this area on the roles of LDHA and LDHB in apoptosis and autophagy of tumor cells. Several examples of how LDHA and LDHB impact on these processes, as well as possible molecular mechanisms, will be discussed in this article. The information included in this review points to the legitimacy of modulating LDHA and/or LDHB to target tumor cells in the context of human and veterinary medicine. Keywords: lactate dehydrogenase A (LDHA); lactate dehydrogenase B (LDHB); apoptosis; autophagy; tumor 1. Lactate Dehydrogenases and Lactate Lactate dehydrogenase [(S)-lactate:NAD+ oxidoreductase; LDH;1; EC 1.1.1.27] comes from a family of NAD+-dependent enzymes. Active LDH is a homo- or heterotetramer molecule, which is assembled by an association of two different subunits: M and H, named as such, since they were originally detected in skeletal muscle (M) and heart (H). In human beings, these polypeptide subunits are encoded by two structurally distinct genes: LDHA (M) and LDHB (H) [1,2]. The LDHA gene is located on chromosome 11, while LDHB is found on chromosome 12. However, chromosomes 1, 2, 4, 9, and 10 apparently contain LDHA gene-related sequences, whereas LDHB gene-related sequences are found in the X chromosome and chromosome 13 [3]. The association of the subunits M and H is random. It generates five isoenzymes LDH1 to LDH5, differing in their subunit proportions and tissue distribution. These isoenzyme subunit compositions are B4, B3A1, B2A2, B1A3, and A4. B4 (LDHB, LDH1, HLDH) has the highest, while A4 (LDHA, LDH5, MLDH) maintains the lowest, electrophoretic migration rate toward the anode [2,4] (Figure1). Int. J. Mol. Sci. 2019, 20, 2085; doi:10.3390/ijms20092085 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 2085 2 of 15 Int. J. Mol. Sci. 2019, 20, x 2 of 15 FigureFigure 1. Lactate 1. Lactate dehydrogenase dehydrogenase (LDH) (LDH) subunits subunits and theirand their combinations. combinations. Lactate Lactate dehydrogenase dehydrogenase (LDH)(LDH) consists consists of two diofff erenttwo subunits:different Lactatesubunits: dehydrogenase Lactate dehydrogenase A (LDHA) and lactateA (LDHA) dehydrogenase and lactate B (LDHB).dehydrogenase LDHA and B LDHB (LDHB). can beLDHA assembled and intoLDHB combinations: can be assembled LDH1 is composedinto combinations: from four LDHB LDH1 is subunits;composed LDH2 from contains four three LDHB LDHB subunits; subunits LDH2 and cont oneains LDHA; three LDH3 LDHB has subunits two LDHB and/LDHA one LDHA; subunits; LDH3 LDH4has possesses two LDHB/LDHA one LDHB subunitsubunits; and LDH4 three possesses LDHA subunits; one LDHB while subunit LDH5 and is composed three LDHA from subunits; four LDHAwhile subunits LDH5 [4 is]. composed Figure conception from four adapted LDHA from subunits Doherty [4]. et Figure al., (2013). conception Graphical adapted elements from adapted Doherty et fromal., Servier (2013). Medical Graphical Art. elements adapted from Servier Medical Art. ExceptExcept for LDHAfor LDHAand andLDHB LDHB, the, LDHCthe LDHC(LDH6, (LDH6, C4, isC4, expressed is expressed in spermatocytes in spermatocytes and and in the in the spermatids)spermatids) and theandLDHD the LDHDgene (expressedgene (expressed in variety in variety of tissue of types) tissue have types) both have also both been also described been described [5–7]. It is[5–7]. thought It is that thoughtLDHA thatand LDHALDHB andascended LDHB fromascended the duplicationfrom the duplicat of a singleion of LDHA-like a single LDHA-likeLDH gene, LDH whilegene,LDHC whileis probably LDHC is aprobably duplication a duplication of the LDHA of thegene LDHA [7]. gene [7]. TheThe human human LDH LDH A-C A-C izoenzymes izoenzymes have have 84–89% 84–89% sequence sequence similarities, similarities, and and 69–75% 69–75% amino amino acid acid identitiesidentities [8]. [8]. TheThe LDHA LDHA and and LDHB LDHB isoforms isoforms occupy occupy mitochondrial mitochondrial compartment, compartment, plasma plasma membrane membrane and and cytosolcytosol [9]. Although[9]. Although LDHA LDHA has a net has charge a net of charge6, and aof higher −6, and affinity a higher for pyruvate affinity (it preferentiallyfor pyruvate (it − + convertspreferentially pyruvate converts to lactate pyruvate and NADH to lactate to NAD and NADH), whereas to NAD LDHB+), whereas has a net LDHB charge has of a+ net1, andcharge a of + higher+1, aandffinity a higher for lactate affinity (preferentially for lactate (preferentially converts lactate converts to pyruvate lactate and to pyruvate NAD to and NADH) NAD [+1 to,7 ],NADH) an experiment[1,7], an withexperiment a stable with long-term a stable knockdown long-term ofknockdown LDHA in MDA-MB-231of LDHA in MDA-MB-231 breast cancer breast cells has cancer showncells lack has of shown changes lack in theirof changes glycolytic in their activity glycolytic (defined activity by the production(defined by of the lactic production acid and ATP)of lactic [10]. acid Accordingand ATP) to other [10]. studies,According neither to other LDHA studies, nor LDHB neither knockout LDHA strongly nor LDHB reduced knockout lactate strongly secretion reduced [1]. Theselactate results secretion indicate [1]. that These LDHB result can spares indicate LDHA that in aLDHB majority can of spare functions LDHA associated in a majority with the of lossfunctions of LDHAassociated [10], and with both the LDHA loss of and LDHA LDHB [10], are and capable both of LDHA the conversion and LDHB of pyruvateare capable to lactateof the conversion [1]. Thus, of a doublepyruvate knockdown to lactate of [1]. LDHA Thus,/B shoulda double be knockdown performed toof validateLDHA/B in should details be how pe theserformed enzymes to validate (all in isoforms)details control how these pivotal enzymes events (all in isof theorms) metabolism control and pivotal production events in of th lactice metabolism acid in tumor and production cells [10]. of Suchlactic an experiment acid in tumor has beencells performed[10]. Such usingan experiment double knockout has been (LDHA performed/B-DKO) using in humandouble colonknockout adenocarcinoma(LDHA/B-DKO) LS174T in human cells and colon mouse adenocarcinoma melanoma B16-F10 LS174T cells, cells which and mouse resulted melanoma in fully-suppressed B16-F10 cells, LDHwhich activity resulted and lack in fully-suppressed of lactate secretion LDH [1]. activity and lack of lactate secretion [1]. ¯ LactateLactate (La ),(La a¯ tricarbonic), a tricarbonic anion, anion, was was discovered discovered and and initially initially described described by Scheele by Scheele [11– 13[11–13].]. It is It is producedproduced in the in cytosolthe cytosol by theby reductionthe reduction of pyruvate of pyruva tote lactate to lactate (pKa (pKa= 3.86) = 3.86) with with the oxidationthe oxidation of of + NADHNADH to NAD to NAD, and+, and this this reaction reaction is catalyzed is catalyzed by LDHA. by LDHA. Then, Then, at cellular at cellular pH, pH, lactic lactic acid acid dissociates dissociates + andand forms forms a lactate a lactate anion anion and and proton proton cation. cation. Lactate Lactate (together (together with with H ) H can+) can be exported be exported from from the cellthe cell (because(because of its of anionic its anionic character, character, it requires it requires a monocarboxylate a monocarboxylate transporter transporter (MCT) (MCT) to cross to cross the cellthe cell membrane)membrane) or/and or/and is converted is converted to pyruvate to pyruvate viathe via LDHB-dependentthe LDHB-dependent reaction reaction [11]. [11]. Overall, the knowledge of the La− production has changed during decades. One might think that pyruvate is the end product of glycolysis, when the O2 is present, while in the case of Int. J. Mol. Sci. 2019, 20, 2085 3 of 15 Overall, the knowledge of the La− production has changed during decades. One might think that pyruvate is the end product of glycolysis, when the O2 is present, while in the case of hypoxia/anoxia, ¯ La− formationInt. J. Mol. Sci. is 2019 observed., 20, x However, recently a bulk of evidence points to La production even3 of if 15 O 2 is delivered to mitochondria. Thus, La−
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