Abstract
Tumor development is influenced by circulating metabolites and most tumors are exposed to substantially elevated levels of lactic acid and low levels of nutrients, such as glucose and glutamine. Tumor-derived lactic acid, the major circulating carbon metabolite, regulates energy metabolism and cancer cell signaling pathways, while also acting as an energy source and signaling molecule. Recent studies have yielded new insights into the pro-tumorigenic action of lactic acid and its metabolism. These insights suggest an anti-tumor therapeutic strategy targeting the oncometabolite lactic acid, with the aim of improving the efficacy and clinical safety of tumor metabolism inhibitors. This review describes the current understanding of the multifunctional roles of tumor lactic acid, as well as therapeutic approaches targeting lactic acid metabolism, including lactate dehydrogenase and monocarboxylate transporters, for anti-cancer therapy.
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Afonso J, Santos LL, Morais A, Amaro T, Longatto-Filho A, Baltazar F (2016) Metabolic coupling in urothelial bladder cancer compartments and its correlation to tumor aggressiveness. Cell Cycle 15:368–380. https://doi.org/10.1080/15384101.2015.1121329
Ahmed K, Tunaru S, Tang C, Muller M, Gille A, Sassmann A, Hanson J, Offermanns S (2010) An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81. Cell Metab 11:311–319. https://doi.org/10.1016/j.cmet.2010.02.012
Angelin A, Gil-De-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, Akimova T, Liu Y, Bhatti TR, Han R, Laskin BL, Baur JA, Blair IA, Wallace DC, Hancock WW, Beier UH (2017) Foxp3 reprograms T cell metabolism to function in low-glucose high-lactate environments. Cell Metab 25:1282-1293 e1287. https://doi.org/10.1016/j.cmet.2016.12.018
Apicella M, Giannoni E, Fiore S, Ferrari KJ, Fernandez-Perez D, Isella C, Granchi C, Minutolo F, Sottile A, Comoglio PM, Medico E, Pietrantonio F, Volante M, Pasini D, Chiarugi P, Giordano S, Corso S (2018) Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab 28:848-865 e846. https://doi.org/10.1016/j.cmet.2018.08.006
Baggstrom MQ, Qi Y, Koczywas M, Argiris A, Johnson EA, Millward MJ, Murphy SC, Erlichman C, Rudin CM, Govindan R, Mayo Phase C, California C (2011) A phase II study of AT-101 (Gossypol) in chemotherapy-sensitive recurrent extensive-stage small cell lung cancer. J Thorac Oncol 6:1757–1760. https://doi.org/10.1097/JTO.0b013e31822e2941
Becker LM, O’connell JT, Vo AP, Cain MP, Tampe D, Bizarro L, Sugimoto H, Mcgow AK, Asara JM, Lovisa S, Mcandrews KM, Zielinski R, Lorenzi PL, Zeisberg M, Raza S, Lebleu VS, Kalluri R (2020) Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep 31:107701. https://doi.org/10.1016/j.celrep.2020.107701
Benjamin D, Robay D, Hindupur SK, Pohlmann J, Colombi M, El-Shemerly MY, Maira SM, Moroni C, Lane HA, Hall MN (2018) Dual inhibition of the lactate transporters MCT1 and MCT4 Is synthetic lethal with metformin due to NAD+ depletion in cancer cells. Cell Rep 25:3047-3058 e3044. https://doi.org/10.1016/j.celrep.2018.11.043
Bhagat TD, Von Ahrens D, Dawlaty M, Zou Y, Baddour J, Achreja A, Zhao H, Yang L, Patel B, Kwak C, Choudhary GS, Gordon-Mitchell S, Aluri S, Bhattacharyya S, Sahu S, Bhagat P, Yu Y, Bartenstein M, Giricz O, Suzuki M, Sohal D, Gupta S, Guerrero PA, Batra S, Goggins M, Steidl U, Greally J, Agarwal B, Pradhan K, Banerjee D, Nagrath D, Maitra A, Verma A (2019) Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts. Elife. https://doi.org/10.7554/eLife.50663
Billiard J, Dennison JB, Briand J, Annan RS, Chai D, Colon M, Dodson CS, Gilbert SA, Greshock J, Jing J, Lu H, Mcsurdy-Freed JE, Orband-Miller LA, Mills GB, Quinn CJ, Schneck JL, Scott GF, Shaw AN, Waitt GM, Wooster RF, Duffy KJ (2013) Quinoline 3-sulfonamides inhibit lactate dehydrogenase A and reverse aerobic glycolysis in cancer cells. Cancer Metab 1:19. https://doi.org/10.1186/2049-3002-1-19
Blatt S, Voelxen N, Sagheb K, Pabst AM, Walenta S, Schroeder T, Mueller-Klieser W, Ziebart T (2016) Lactate as a predictive marker for tumor recurrence in patients with head and neck squamous cell carcinoma (HNSCC) post radiation: a prospective study over 15 years. Clin Oral Investig 20:2097–2104. https://doi.org/10.1007/s00784-015-1699-6
Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, Aranda Lopez P, Hahlbrock J, Muth S, Endo S, Pektor S, Brand A, Renner K, Popp V, Gerlach K, Vogel D, Lueckel C, Arnold-Schild D, Pouyssegur J, Kreutz M, Huber M, Koenig J, Weigmann B, Probst HC, Von Stebut E, Becker C, Schild H, Schmitt E, Bopp T (2018) Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol 19:1319–1329. https://doi.org/10.1038/s41590-018-0226-8
Bonglack EN, Messinger JE, Cable JM, Ch’ng J, Parnell KM, Reinoso-Vizcaino NM, Barry AP, Russell VS, Dave SS, Christofk HR, Luftig MA (2021) Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2022495118
Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP (2010) Ketones and lactate “fuel” tumor growth and metastasis: evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle 9:3506–3514. https://doi.org/10.4161/cc.9.17.12731
Boudreau A, Purkey HE, Hitz A, Robarge K, Peterson D, Labadie S, Kwong M, Hong R, Gao M, Del Nagro C, Pusapati R, Ma S, Salphati L, Pang J, Zhou A, Lai T, Li Y, Chen Z, Wei B, Yen I, Sideris S, Mccleland M, Firestein R, Corson L, Vanderbilt A, Williams S, Daemen A, Belvin M, Eigenbrot C, Jackson PK, Malek S, Hatzivassiliou G, Sampath D, Evangelista M, O’brien T, (2016) Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition. Nat Chem Biol 12:779–786. https://doi.org/10.1038/nchembio.2143
Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M (2016) LDHA-Associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:657–671. https://doi.org/10.1016/j.cmet.2016.08.011
Brisson L, Banski P, Sboarina M, Dethier C, Danhier P, Fontenille MJ, Van Hee VF, Vazeille T, Tardy M, Falces J, Bouzin C, Porporato PE, Frederick R, Michiels C, Copetti T, Sonveaux P (2016) Lactate dehydrogenase b controls lysosome activity and autophagy in cancer. Cancer Cell 30:418–431. https://doi.org/10.1016/j.ccell.2016.08.005
Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW, Mueller-Klieser W (2001) Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys 51:349–353. https://doi.org/10.1016/s0360-3016(01)01630-3
Broer S, Schneider HP, Broer A, Rahman B, Hamprecht B, Deitmer JW (1998) Characterization of the monocarboxylate transporter 1 expressed in Xenopus laevis oocytes by changes in cytosolic pH. Biochem J 333(1):167–174. https://doi.org/10.1042/bj3330167
Brooks GA (1998) Mammalian fuel utilization during sustained exercise. Comp Biochem Physiol B Biochem Mol Biol 120:89–107. https://doi.org/10.1016/s0305-0491(98)00025-x
Brooks GA (2009) Cell-cell and intracellular lactate shuttles. J Physiol 587:5591–5600. https://doi.org/10.1113/jphysiol.2009.178350
Byun JK, Park M, Yun JW, Lee J, Kim JS, Cho SJ, Lee YM, Lee IK, Choi YK, Park KG (2019) Oncogenic KRAS signaling activates mTORC1 through COUP-TFII-mediated lactate production. EMBO Rep. https://doi.org/10.15252/embr.201847451
Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, Canese R, Jachetti E, Rossetti M, Huber V, Parmiani G, Generoso L, Santinami M, Borghi M, Fais S, Bellone M, Rivoltini L (2012) Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 72:2746–2756. https://doi.org/10.1158/0008-5472.CAN-11-1272
Caronni N, Simoncello F, Stafetta F, Guarnaccia C, Ruiz-Moreno JS, Opitz B, Galli T, Proux-Gillardeaux V, Benvenuti F (2018) Downregulation of membrane trafficking proteins and lactate conditioning determine loss of dendritic cell function in lung cancer. Cancer Res 78:1685–1699. https://doi.org/10.1158/0008-5472.CAN-17-1307
Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’sullivan D, Huang SC, Van Der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239–1251. https://doi.org/10.1016/j.cell.2013.05.016
Chen P, Zuo H, Xiong H, Kolar MJ, Chu Q, Saghatelian A, Siegwart DJ, Wan Y (2017) Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis. Proc Natl Acad Sci USA 114:580–585. https://doi.org/10.1073/pnas.1614035114
Cheng WY, Huynh H, Chen P, Pena-Llopis S, Wan Y (2016) Macrophage PPARgamma inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone. Elife. https://doi.org/10.7554/eLife.18501
Cluntun AA, Badolia R, Lettlova S, Parnell KM, Shankar TS, Diakos NA, Olson KA, Taleb I, Tatum SM, Berg JA, Cunningham CN, Van Ry T, Bott AJ, Krokidi AT, Fogarty S, Skedros S, Swiatek WI, Yu X, Luo B, Merx S, Navankasattusas S, Cox JE, Ducker GS, Holland WL, Mckellar SH, Rutter J, Drakos SG (2021) The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab 33:629-648 e610. https://doi.org/10.1016/j.cmet.2020.12.003
Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R (2014) Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–563. https://doi.org/10.1038/nature13490
Comito G, Iscaro A, Bacci M, Morandi A, Ippolito L, Parri M, Montagnani I, Raspollini MR, Serni S, Simeoni L, Giannoni E, Chiarugi P (2019) Lactate modulates CD4(+) T-cell polarization and induces an immunosuppressive environment, which sustains prostate carcinoma progression via TLR8/miR21 axis. Oncogene 38:3681–3695. https://doi.org/10.1038/s41388-019-0688-7
Courtney KD, Bezwada D, Mashimo T, Pichumani K, Vemireddy V, Funk AM, Wimberly J, Mcneil SS, Kapur P, Lotan Y, Margulis V, Cadeddu JA, Pedrosa I, Deberardinis RJ, Malloy CR, Bachoo RM, Maher EA (2018) Isotope tracing of human clear cell renal cell carcinomas demonstrates suppressed glucose oxidation in vivo. Cell Metab 28:793-800 e792. https://doi.org/10.1016/j.cmet.2018.07.020
Critchlow SE, Hopcroft L, Mooney L, Curtis N, Whalley N, Zhong H, Logie A, Revill M, Xie L, Zhang JJCR (2012) Pre-clinical targeting of the metabolic phenotype of lymphoma by AZD3965, a selective inhibitor of monocarboxylate transporter 1 (MCT1). Cancer Res 72:3224. https://doi.org/10.1158/1538-7445.AM2012-3224
Daw CC, Ramachandran K, Enslow BT, Maity S, Bursic B, Novello MJ, Rubannelsonkumar CS, Mashal AH, Ravichandran J, Bakewell TM, Wang W, Li K, Madaris TR, Shannon CE, Norton L, Kandala S, Caplan J, Srikantan S, Stathopulos PB, Reeves WB, Madesh M (2020) Lactate elicits ER-Mitochondrial Mg(2+) dynamics to integrate cellular metabolism. Cell 183:474-489 e417. https://doi.org/10.1016/j.cell.2020.08.049
De La Cruz-Lopez KG, Castro-Munoz LJ, Reyes-Hernandez DO, Garcia-Carranca A, Manzo-Merino J (2019) Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front Oncol 9:1143. https://doi.org/10.3389/fonc.2019.01143
De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P (2012) Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS ONE 7:e46571. https://doi.org/10.1371/journal.pone.0046571
Dimmer KS, Friedrich B, Lang F, Deitmer JW, Broer S (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 350(Pt 1):219–227
Doherty JR, Cleveland JL (2013) Targeting lactate metabolism for cancer therapeutics. J Clin Invest 123:3685–3692. https://doi.org/10.1172/JCI69741
Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18:884–901. https://doi.org/10.1016/j.devcel.2010.05.012
Eichner R, Heider M, Fernandez-Saiz V, Van Bebber F, Garz AK, Lemeer S, Rudelius M, Targosz BS, Jacobs L, Knorn AM, Slawska J, Platzbecker U, Germing U, Langer C, Knop S, Einsele H, Peschel C, Haass C, Keller U, Schmid B, Gotze KS, Kuster B, Bassermann F (2016) Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat Med 22:735–743. https://doi.org/10.1038/nm.4128
Ekberg H, Qi Z, Pahlman C, Veress B, Bundick RV, Craggs RI, Holness E, Edwards S, Murray CM, Ferguson D, Kerry PJ, Wilson E, Donald DK (2007) The specific monocarboxylate transporter-1 (MCT-1) inhibitor, AR-C117977, induces donor-specific suppression, reducing acute and chronic allograft rejection in the rat. Transplantation 84:1191–1199. https://doi.org/10.1097/01.tp.0000287541.53389.be
Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, Bailey K, Balagurunathan Y, Rothberg JM, Sloane BF, Johnson J, Gatenby RA, Gillies RJ (2013) Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 73:1524–1535. https://doi.org/10.1158/0008-5472.CAN-12-2796
Fang Y, Liu W, Tang Z, Ji X, Zhou Y, Song S, Tian M, Tao C, Huang R, Zhu G, Jiang X, Gao J, Qu W, Wang H, Zhou P, Wu X, Jin L, Sun H, Ding Z, Peng Y, Zhao S, Zhou J, Fan J, Xu W, Shi Y (2022) Monocarboxylate transporter 4 inhibition potentiates hepatocellular carcinoma immunotherapy through enhancing T cell infiltration and immune attack. Hepatology. https://doi.org/10.1002/hep.32348
Faubert B, Li KY, Cai L, Hensley CT, Kim J, Zacharias LG, Yang C, Do QN, Doucette S, Burguete D, Li H, Huet G, Yuan Q, Wigal T, Butt Y, Ni M, Torrealba J, Oliver D, Lenkinski RE, Malloy CR, Wachsmann JW, Young JD, Kernstine K, Deberardinis RJ (2017) Lactate metabolism in human lung tumors. Cell 171:358-371 e359. https://doi.org/10.1016/j.cell.2017.09.019
Felmlee MA, Jones RS, Rodriguez-Cruz V, Follman KE, Morris ME (2020) Monocarboxylate transporters (SLC16): function, regulation, and role in health and disease. Pharmacol Rev 72:466–485. https://doi.org/10.1124/pr.119.018762
Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z (2017) Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 36:5829–5839. https://doi.org/10.1038/onc.2017.188
Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y (2018) Lactate dehydrogenase A: a key player in carcinogenesis and potential target in cancer therapy. Cancer Med 7:6124–6136. https://doi.org/10.1002/cam4.1820
Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, Lanciotti M, Serni S, Cirri P, Chiarugi P (2012) Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res 72:5130–5140. https://doi.org/10.1158/0008-5472.CAN-12-1949
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW, Kreutz M (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819. https://doi.org/10.1182/blood-2006-07-035972
Fiume L (1960) Inhibition of aerobic glycolysis in Yoshida ascites hepatoma by tartronic acid. Nature 187:792–793. https://doi.org/10.1038/187792a0
Fletcher JW, Djulbegovic B, Soares HP, Siegel BA, Lowe VJ, Lyman GH, Coleman RE, Wahl R, Paschold JC, Avril N, Einhorn LH, Suh WW, Samson D, Delbeke D, Gorman M, Shields AF (2008) Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 49:480–508. https://doi.org/10.2967/jnumed.107.047787
Fu S, He K, Tian C, Sun H, Zhu C, Bai S, Liu J, Wu Q, Xie D, Yue T, Shen Z, Dai Q, Yu X, Zhu S, Liu G, Zhou R, Duan S, Tian Z, Xu T, Wang H, Bai L (2020) Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells. Nat Commun 11:438. https://doi.org/10.1038/s41467-020-14332-x
Giusti I, D’ascenzo S, Millimaggi D, Taraboletti G, Carta G, Franceschini N, Pavan A, Dolo V (2008) Cathepsin B mediates the pH-dependent proinvasive activity of tumor-shed microvesicles. Neoplasia 10:481–488. https://doi.org/10.1593/neo.08178
Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A, Kreutz M (2006) Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood 107:2013–2021. https://doi.org/10.1182/blood-2005-05-1795
Granchi C, Roy S, Giacomelli C, Macchia M, Tuccinardi T, Martinelli A, Lanza M, Betti L, Giannaccini G, Lucacchini A, Funel N, Leon LG, Giovannetti E, Peters GJ, Palchaudhuri R, Calvaresi EC, Hergenrother PJ, Minutolo F (2011) Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. J Med Chem 54:1599–1612. https://doi.org/10.1021/jm101007q
Granchi C, Paterni I, Rani R, Minutolo F (2013) Small-molecule inhibitors of human LDH5. Future Med Chem 5:1967–1991. https://doi.org/10.4155/fmc.13.151
Halestrap AP (2013) Monocarboxylic acid transport. Compr Physiol 3:1611–1643. https://doi.org/10.1002/cphy.c130008
Halestrap AP, Price NT (1999) The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 343(2):281–299
Halford SE, Walter H, Mckay P, Townsend W, Linton K, Heinzmann K, Dragoni I, Brotherton L, Veal G, Siskos A (2021) Phase I expansion study of the first-in-class monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). J Clin Oncol 39:3115. https://doi.org/10.1200/JCO.2021.39.15_suppl.3115
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. https://doi.org/10.1016/j.cell.2011.02.013
Hensley CT, Faubert B, Yuan Q, Lev-Cohain N, Jin E, Kim J, Jiang L, Ko B, Skelton R, Loudat L, Wodzak M, Klimko C, Mcmillan E, Butt Y, Ni M, Oliver D, Torrealba J, Malloy CR, Kernstine K, Lenkinski RE, Deberardinis RJ (2016) Metabolic Heterogeneity in Human Lung Tumors. Cell 164:681–694. https://doi.org/10.1016/j.cell.2015.12.034
Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F, Wedemeyer H, Lehner F, Manns MP, Greten TF, Korangy F (2009) Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807. https://doi.org/10.1002/hep.23054
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Le Z, Yanxiang Guo J, White E, Rabinowitz JD (2017) Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–118. https://doi.org/10.1038/nature24057
Ihara Y, Kihara Y, Hamano F, Yanagida K, Morishita Y, Kunita A, Yamori T, Fukayama M, Aburatani H, Shimizu T, Ishii S (2010) The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor. Proc Natl Acad Sci U S A 107:17309–17314. https://doi.org/10.1073/pnas.1001165107
Ikeda M (1990) Inhibition kinetics of NAD-linked enzymes by gossypol acetic acid. Andrologia 22:409–416. https://doi.org/10.1111/j.1439-0272.1990.tb02019.x
Ishihara S, Hata K, Hirose K, Okui T, Toyosawa S, Uzawa N, Nishimura R, Yoneda T (2022) The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer. Sci Rep 12:6261. https://doi.org/10.1038/s41598-022-10143-w
Jaroszewski JW, Strom-Hansen T, Hansen SH, Thastrup O, Kofod H (1992) On the botanical distribution of chiral forms of gossypol. Planta Med 58:454–458. https://doi.org/10.1055/s-2006-961512
Jiang J, Huang D, Jiang Y, Hou J, Tian M, Li J, Sun L, Zhang Y, Zhang T, Li Z, Li Z, Tong S, Ma Y (2021) Lactate modulates cellular metabolism through histone lactylation-mediated gene expression in non-small cell lung cancer. Front Oncol 11:647559. https://doi.org/10.3389/fonc.2021.647559
Jin Z, Lu Y, Wu X, Pan T, Yu Z, Hou J, Wu A, Li J, Yang Z, Li C, Yan M, Yan C, Zhu Z, Liu B, Qiu W, Su L (2021) The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer. Redox Biol 46:102076. https://doi.org/10.1016/j.redox.2021.102076
Jing Z, Xu H, Chen X, Zhong Q, Huang J, Zhang Y, Guo W, Yang Z, Ding S, Chen P, Huang Z (2016) The proton-sensing G-protein coupled receptor GPR4 promotes angiogenesis in head and neck cancer. PLoS ONE 11:e0152789. https://doi.org/10.1371/journal.pone.0152789
Kallinowski F, Vaupel P (1986) Concurrent measurements of O2 partial pressures and pH values in human mammary carcinoma xenotransplants. Adv Exp Med Biol 200:609–621. https://doi.org/10.1007/978-1-4684-5188-7_74
Kato Y, Lambert CA, Colige AC, Mineur P, Noel A, Frankenne F, Foidart JM, Baba M, Hata R, Miyazaki K, Tsukuda M (2005) Acidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signaling. J Biol Chem 280:10938–10944. https://doi.org/10.1074/jbc.M411313200
Kennedy KM, Scarbrough PM, Ribeiro A, Richardson R, Yuan H, Sonveaux P, Landon CD, Chi JT, Pizzo S, Schroeder T, Dewhirst MW (2013) Catabolism of exogenous lactate reveals it as a legitimate metabolic substrate in breast cancer. PLoS ONE 8:e75154. https://doi.org/10.1371/journal.pone.0075154
Kimura H, Braun RD, Ong ET, Hsu R, Secomb TW, Papahadjopoulos D, Hong K, Dewhirst MW (1996) Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res 56:5522–5528
Kobayashi M, Otsuka Y, Itagaki S, Hirano T, Iseki K (2006) Inhibitory effects of statins on human monocarboxylate transporter 4. Int J Pharm 317:19–25. https://doi.org/10.1016/j.ijpharm.2006.02.043
Koukourakis MI, Giatromanolaki A, Harris AL, Sivridis E (2006) Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res 66:632–637. https://doi.org/10.1158/0008-5472.CAN-05-3260
Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H (2022) Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 40:201-218 e209. https://doi.org/10.1016/j.ccell.2022.01.001
Latham T, Mackay L, Sproul D, Karim M, Culley J, Harrison DJ, Hayward L, Langridge-Smith P, Gilbert N, Ramsahoye BH (2012) Lactate, a product of glycolytic metabolism, inhibits histone deacetylase activity and promotes changes in gene expression. Nucleic Acids Res 40:4794–4803. https://doi.org/10.1093/nar/gks066
Le Floch R, Chiche J, Marchiq I, Naiken T, Ilc K, Murray CM, Critchlow SE, Roux D, Simon MP, Pouyssegur J (2011) CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA 108:16663–16668. https://doi.org/10.1073/pnas.1106123108
Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL, Dang CV (2010) Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA 107:2037–2042. https://doi.org/10.1073/pnas.0914433107
Lee DC, Sohn HA, Park ZY, Oh S, Kang YK, Lee KM, Kang M, Jang YJ, Yang SJ, Hong YK, Noh H, Kim JA, Kim DJ, Bae KH, Kim DM, Chung SJ, Yoo HS, Yu DY, Park KC, Yeom YI (2015) A lactate-induced response to hypoxia. Cell 161:595–609. https://doi.org/10.1016/j.cell.2015.03.011
Lee YJ, Shin KJ, Park SA, Park KS, Park S, Heo K, Seo YK, Noh DY, Ryu SH, Suh PG (2016) G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion. Oncotarget 7:70898–70911. https://doi.org/10.18632/oncotarget.12286
Li X, Zhang Z, Zhang Y, Cao Y, Wei H, Wu Z (2018) Upregulation of lactate-inducible snail protein suppresses oncogene-mediated senescence through p16(INK4a) inactivation. J Exp Clin Cancer Res 37:39. https://doi.org/10.1186/s13046-018-0701-y
Li N, Kang Y, Wang L, Huff S, Tang R, Hui H, Agrawal K, Gonzalez GM, Wang Y, Patel SP, Rana TM (2020) ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci USA 117:20159–20170. https://doi.org/10.1073/pnas.1918986117
Liao R, Ren G, Liu H, Chen X, Cao Q, Wu X, Li J, Dong C (2018) ME1 promotes basal-like breast cancer progression and associates with poor prognosis. Sci Rep 8:16743. https://doi.org/10.1038/s41598-018-35106-y
Liu G, Kelly WK, Wilding G, Leopold L, Brill K, Somer B (2009) An open-label, multicenter, phase I/II study of single-agent AT-101 in men with castrate-resistant prostate cancer. Clin Cancer Res 15:3172–3176. https://doi.org/10.1158/1078-0432.CCR-08-2985
Liu N, Luo J, Kuang D, Xu S, Duan Y, Xia Y, Wei Z, Xie X, Yin B, Chen F, Luo S, Liu H, Wang J, Jiang K, Gong F, Tang ZH, Cheng X, Li H, Li Z, Laurence A, Wang G, Yang XP (2019) Lactate inhibits ATP6V0d2 expression in tumor-associated macrophages to promote HIF-2alpha-mediated tumor progression. J Clin Invest 129:631–646. https://doi.org/10.1172/JCI123027
Long Y, Gao Z, Hu X, Xiang F, Wu Z, Zhang J, Han X, Yin L, Qin J, Lan L, Yin F, Wang Y (2018) Downregulation of MCT4 for lactate exchange promotes the cytotoxicity of NK cells in breast carcinoma. Cancer Med 7:4690–4700. https://doi.org/10.1002/cam4.1713
Lu H, Dalgard CL, Mohyeldin A, Mcfate T, Tait AS, Verma A (2005) Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1. J Biol Chem 280:41928–41939. https://doi.org/10.1074/jbc.M508718200
Maekawa M, Sudo K, Kanno T, Li SS (1990) Molecular characterization of genetic mutation in human lactate dehydrogenase-A (M) deficiency. Biochem Biophys Res Commun 168:677–682. https://doi.org/10.1016/0006-291x(90)92374-9
Maher EA, Marin-Valencia I, Bachoo RM, Mashimo T, Raisanen J, Hatanpaa KJ, Jindal A, Jeffrey FM, Choi C, Madden C, Mathews D, Pascual JM, Mickey BE, Malloy CR, Deberardinis RJ (2012) Metabolism of [U-13 C]glucose in human brain tumors in vivo. NMR Biomed 25:1234–1244. https://doi.org/10.1002/nbm.2794
Makinoshima H, Takita M, Matsumoto S, Yagishita A, Owada S, Esumi H, Tsuchihara K (2014) Epidermal growth factor receptor (EGFR) signaling regulates global metabolic pathways in EGFR-mutated lung adenocarcinoma. J Biol Chem 289:20813–20823. https://doi.org/10.1074/jbc.M114.575464
Manerba M, Vettraino M, Fiume L, Di Stefano G, Sartini A, Giacomini E, Buonfiglio R, Roberti M, Recanatini M (2012) Galloflavin (CAS 568–80-9): a novel inhibitor of lactate dehydrogenase. ChemMedChem 7:311–317. https://doi.org/10.1002/cmdc.201100471
Markert CL (1963) Lactate dehydrogenase isozymes: dissociation and recombination of subunits. Science 140:1329–1330. https://doi.org/10.1126/science.140.3573.1329
Martin GR, Jain RK (1994) Noninvasive measurement of interstitial pH profiles in normal and neoplastic tissue using fluorescence ratio imaging microscopy. Cancer Res 54:5670–5674
Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP (2011) Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol 43:1045–1051. https://doi.org/10.1016/j.biocel.2011.01.023
Mccleland ML, Adler AS, Shang Y, Hunsaker T, Truong T, Peterson D, Torres E, Li L, Haley B, Stephan JP, Belvin M, Hatzivassiliou G, Blackwood EM, Corson L, Evangelista M, Zha J, Firestein R (2012) An integrated genomic screen identifies LDHB as an essential gene for triple-negative breast cancer. Cancer Res 72:5812–5823. https://doi.org/10.1158/0008-5472.CAN-12-1098
Mccleland ML, Adler AS, Deming L, Cosino E, Lee L, Blackwood EM, Solon M, Tao J, Li L, Shames D, Jackson E, Forrest WF, Firestein R (2013) Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. Clin Cancer Res 19:773–784. https://doi.org/10.1158/1078-0432.CCR-12-2638
Mcneillis R, Greystoke A, Walton J, Bacon C, Keun H, Siskos A, Petrides G, Leech N, Jenkinson F, Bowron A, Halford S, Plummer R (2020) A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965. Br J Cancer 122:1141–1145. https://doi.org/10.1038/s41416-020-0727-8
Mintun MA, Vlassenko AG, Rundle MM, Raichle ME (2004) Increased lactate/pyruvate ratio augments blood flow in physiologically activated human brain. Proc Natl Acad Sci USA 101:659–664. https://doi.org/10.1073/pnas.0307457100
Miranda-Goncalves V, Bezerra F, Costa-Almeida R, Freitas-Cunha M, Soares R, Martinho O, Reis RM, Pinheiro C, Baltazar F (2017) Monocarboxylate transporter 1 is a key player in glioma-endothelial cell crosstalk. Mol Carcinog 56:2630–2642. https://doi.org/10.1002/mc.22707
Mu X, Shi W, Xu Y, Xu C, Zhao T, Geng B, Yang J, Pan J, Hu S, Zhang C, Zhang J, Wang C, Shen J, Che Y, Liu Z, Lv Y, Wen H, You Q (2018) Tumor-derived lactate induces M2 macrophage polarization via the activation of the ERK/STAT3 signaling pathway in breast cancer. Cell Cycle 17:428–438. https://doi.org/10.1080/15384101.2018.1444305
Nadal-Bufi F, Mason JM, Chan LY, Craik DJ, Kaas Q, Troeira Henriques S (2021) Designed beta-Hairpins Inhibit LDH5 oligomerization and enzymatic activity. J Med Chem 64:3767–3779. https://doi.org/10.1021/acs.jmedchem.0c01898
Nagaraj S, Gupta K, Pisarev V, Kinarsky L, Sherman S, Kang L, Herber DL, Schneck J, Gabrilovich DI (2007) Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat Med 13:828–835. https://doi.org/10.1038/nm1609
Okumura N, Terasawa F, Ueno I, Oki K, Yamauchi K, Hidaka H, Tozuka M, Okura M, Katsuyama T (1999) Genetic analyses in homozygous and heterozygous variants of lactate dehydrogenase-B (H) subunit–LD-B Matsumoto I and II (LD-B W323R). Clin Chim Acta 287:163–171. https://doi.org/10.1016/s0009-8981(99)00127-8
Oshima N, Ishida R, Kishimoto S, Beebe K, Brender JR, Yamamoto K, Urban D, Rai G, Johnson MS, Benavides G, Squadrito GL, Crooks D, Jackson J, Joshi A, Mott BT, Shrimp JH, Moses MA, Lee MJ, Yuno A, Lee TD, Hu X, Anderson T, Kusewitt D, Hathaway HH, Jadhav A, Picard D, Trepel JB, Mitchell JB, Stott GM, Moore W, Simeonov A, Sklar LA, Norenberg JP, Linehan WM, Maloney DJ, Dang CV, Waterson AG, Hall M, Darley-Usmar VM, Krishna MC, Neckers LM (2020) Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep 30:1798-1810 e1794. https://doi.org/10.1016/j.celrep.2020.01.039
Ovens MJ, Davies AJ, Wilson MC, Murray CM, Halestrap AP (2010) AR-C155858 is a potent inhibitor of monocarboxylate transporters MCT1 and MCT2 that binds to an intracellular site involving transmembrane helices 7–10. Biochem J 425:523–530. https://doi.org/10.1042/BJ20091515
Paget S (1989) The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev 8:98–101. https://doi.org/10.1016/S0140-6736(00)49915-0
Pahlman C, Qi Z, Murray CM, Ferguson D, Bundick RV, Donald DK, Ekberg H (2013) Immunosuppressive properties of a series of novel inhibitors of the monocarboxylate transporter MCT-1. Transpl Int 26:22–29. https://doi.org/10.1111/j.1432-2277.2012.01579.x
Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, Divino CM, Chen SH (2010) Immune stimulatory receptor CD40 is required for T-cell suppression and T regulatory cell activation mediated by myeloid-derived suppressor cells in cancer. Cancer Res 70:99–108. https://doi.org/10.1158/0008-5472.CAN-09-1882
Pan L, Feng F, Wu J, Fan S, Han J, Wang S, Yang L, Liu W, Wang C, Xu K (2022) Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharmacol Res 181:106270. https://doi.org/10.1016/j.phrs.2022.106270
Papaconstantinou J, Colowick SP (1961) The role of glycolysis in the growth of tumor cells. II. The effect of oxamic acid on the growth of HeLa cells in tissue culture. J Biol Chem 236:285–288
Park S, Chang CY, Safi R, Liu X, Baldi R, Jasper JS, Anderson GR, Liu T, Rathmell JC, Dewhirst MW, Wood KC, Locasale JW, Mcdonnell DP (2016) ERRalpha-regulated lactate metabolism contributes to resistance to targeted therapies in breast cancer. Cell Rep 15:323–335. https://doi.org/10.1016/j.celrep.2016.03.026
Payen VL, Mina E, Van Hee VF, Porporato PE, Sonveaux P (2020) Monocarboxylate transporters in cancer. Mol Metab 33:48–66. https://doi.org/10.1016/j.molmet.2019.07.006
Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO (2016) Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354:481–484. https://doi.org/10.1126/science.aaf6284
Perez-Escuredo J, Dadhich RK, Dhup S, Cacace A, Van Hee VF, De Saedeleer CJ, Sboarina M, Rodriguez F, Fontenille MJ, Brisson L, Porporato PE, Sonveaux P (2016) Lactate promotes glutamine uptake and metabolism in oxidative cancer cells. Cell Cycle 15:72–83. https://doi.org/10.1080/15384101.2015.1120930
Pertega-Gomes N, Vizcaino JR, Attig J, Jurmeister S, Lopes C, Baltazar F (2014) A lactate shuttle system between tumour and stromal cells is associated with poor prognosis in prostate cancer. BMC Cancer 14:352. https://doi.org/10.1186/1471-2407-14-352
Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mule JJ, Ibrahim-Hashim A, Gillies RJ (2016) Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res 76:1381–1390. https://doi.org/10.1158/0008-5472.CAN-15-1743
Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess C, Christofori G (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15:1161–1174. https://doi.org/10.1016/j.celrep.2016.04.028
Poole RC, Halestrap AP (1993) Transport of lactate and other monocarboxylates across mammalian plasma membranes. Am J Physiol 264:C761-782. https://doi.org/10.1152/ajpcell.1993.264.4.C761
Quanz M, Bender E, Kopitz C, Grunewald S, Schlicker A, Schwede W, Eheim A, Toschi L, Neuhaus R, Richter C, Toedling J, Merz C, Lesche R, Kamburov A, Siebeneicher H, Bauser M, Hagebarth A (2018) Preclinical efficacy of the novel monocarboxylate transporter 1 inhibitor BAY-8002 and associated markers of resistance. Mol Cancer Ther 17:2285–2296. https://doi.org/10.1158/1535-7163.MCT-17-1253
Quinn WJ 3rd, Jiao J, Teslaa T, Stadanlick J, Wang Z, Wang L, Akimova T, Angelin A, Schafer PM, Cully MD, Perry C, Kopinski PK, Guo L, Blair IA, Ghanem LR, Leibowitz MS, Hancock WW, Moon EK, Levine MH, Eruslanov EB, Wallace DC, Baur JA, Beier UH (2020) Lactate limits T cell proliferation via the NAD(H) Redox State. Cell Rep 33:108500. https://doi.org/10.1016/j.celrep.2020.108500
Rabinowitz JD, Enerback S (2020) Lactate: the ugly duckling of energy metabolism. Nat Metab 2:566–571. https://doi.org/10.1038/s42255-020-0243-4
Rattigan YI, Patel BB, Ackerstaff E, Sukenick G, Koutcher JA, Glod JW, Banerjee D (2012) Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment. Exp Cell Res 318:326–335. https://doi.org/10.1016/j.yexcr.2011.11.014
Raychaudhuri D, Bhattacharya R, Sinha BP, Liu CSC, Ghosh AR, Rahaman O, Bandopadhyay P, Sarif J, D’rozario R, Paul S, Das A, Sarkar DK, Chattopadhyay S, Ganguly D (2019) Lactate induces pro-tumor reprogramming in intratumoral plasmacytoid dendritic cells. Front Immunol 10:1878. https://doi.org/10.3389/fimmu.2019.01878
Read JA, Winter VJ, Eszes CM, Sessions RB, Brady RL (2001) Structural basis for altered activity of M- and H-isozyme forms of human lactate dehydrogenase. Proteins 43:175–185. https://doi.org/10.1002/1097-0134(20010501)43:2%3c175::aid-prot1029%3e3.0.co;2-#
Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, Menevse AN, Kauer N, Blazquez R, Hacker L, Decking SM, Bohn T, Faerber S, Evert K, Aigle L, Amslinger S, Landa M, Krijgsman O, Rozeman EA, Brummer C, Siska PJ, Singer K, Pektor S, Miederer M, Peter K, Gottfried E, Herr W, Marchiq I, Pouyssegur J, Roush WR, Ong S, Warren S, Pukrop T, Beckhove P, Lang SA, Bopp T, Blank CU, Cleveland JL, Oefner PJ, Dettmer K, Selby M, Kreutz M (2019) Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep 29:135-150 e139. https://doi.org/10.1016/j.celrep.2019.08.068
Renner O, Mayer M, Leischner C, Burkard M, Berger A, Lauer UM, Venturelli S, Bischoff SC (2022) Systematic review of gossypol/AT-101 in cancer clinical trials. Pharmaceuticals (basel). https://doi.org/10.3390/ph15020144
Roland CL, Arumugam T, Deng D, Liu SH, Philip B, Gomez S, Burns WR, Ramachandran V, Wang H, Cruz-Monserrate Z, Logsdon CD (2014) Cell surface lactate receptor GPR81 is crucial for cancer cell survival. Cancer Res 74:5301–5310. https://doi.org/10.1158/0008-5472.CAN-14-0319
Semenza GL, Roth PH, Fang HM, Wang GL (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J Biol Chem 269:23757–23763. https://doi.org/10.1016/S0021-9258(17)31580-6
Shan T, Chen S, Chen X, Lin WR, Li W, Ma J, Wu T, Cui X, Ji H, Li Y, Kang Y (2017) Cancer-associated fibroblasts enhance pancreatic cancer cell invasion by remodeling the metabolic conversion mechanism. Oncol Rep 37:1971–1979. https://doi.org/10.3892/or.2017.5479
Shangguan C, Gan G, Zhang J, Wu J, Miao Y, Zhang M, Li B, Mi J (2018) Cancer-associated fibroblasts enhance tumor (18)F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT. Theranostics 8:1376–1388. https://doi.org/10.7150/thno.22717
Sheppard S, Santosa EK, Lau CM, Violante S, Giovanelli P, Kim H, Cross JR, Li MO, Sun JC (2021) Lactate dehydrogenase A-dependent aerobic glycolysis promotes natural killer cell anti-viral and anti-tumor function. Cell Rep 35:109210. https://doi.org/10.1016/j.celrep.2021.109210
Shibata S, Sogabe S, Miwa M, Fujimoto T, Takakura N, Naotsuka A, Kitamura S, Kawamoto T, Soga T (2021) Identification of the first highly selective inhibitor of human lactate dehydrogenase B. Sci Rep 11:21353. https://doi.org/10.1038/s41598-021-00820-7
Shim H, Dolde C, Lewis BC, Wu CS, Dang G, Jungmann RA, Dalla-Favera R, Dang CV (1997) c-Myc transactivation of LDH-A: implications for tumor metabolism and growth. Proc Natl Acad Sci USA 94:6658–6663. https://doi.org/10.1073/pnas.94.13.6658
Silva A, Antunes B, Batista A, Pinto-Ribeiro F, Baltazar F, Afonso J (2021) In vivo anticancer activity of AZD3965: a systematic review. Molecules. https://doi.org/10.3390/molecules27010181
Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, Depinho RA, Cantley LC, Kimmelman AC (2013) Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496:101–105. https://doi.org/10.1038/nature12040
Sonveaux P, Vegran F, Schroeder T, Wergin MC, Verrax J, Rabbani ZN, De Saedeleer CJ, Kennedy KM, Diepart C, Jordan BF, Kelley MJ, Gallez B, Wahl ML, Feron O, Dewhirst MW (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 118:3930–3942. https://doi.org/10.1172/JCI36843
Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS ONE 7:e33418. https://doi.org/10.1371/journal.pone.0033418
Srivastava DK, Bernhard SA (1987) Biophysical chemistry of metabolic reaction sequences in concentrated enzyme solution and in the cell. Annu Rev Biophys Biophys Chem 16:175–204. https://doi.org/10.1146/annurev.bb.16.060187.001135
Sudo K, Maekawa M, Houki N, Okuda T, Akizuki S, Magara T, Kawano K (1999) A novel in-frame deletion mutation in a case of lactate dehydrogenase (LD) H subunit deficiency showing an atypical LD isoenzyme pattern in serum and erythrocytes. Clin Biochem 32:137–141. https://doi.org/10.1016/s0009-9120(98)00097-6
Sun K, Tang S, Hou Y, Xi L, Chen Y, Yin J, Peng M, Zhao M, Cui X, Liu M (2019) Oxidized ATM-mediated glycolysis enhancement in breast cancer-associated fibroblasts contributes to tumor invasion through lactate as metabolic coupling. EBioMedicine 41:370–383. https://doi.org/10.1016/j.ebiom.2019.02.025
Tasdogan A, Faubert B, Ramesh V, Ubellacker JM, Shen B, Solmonson A, Murphy MM, Gu Z, Gu W, Martin M, Kasitinon SY, Vandergriff T, Mathews TP, Zhao Z, Schadendorf D, Deberardinis RJ, Morrison SJ (2020) Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577:115–120. https://doi.org/10.1038/s41586-019-1847-2
Thabault L, Brisson L, Brustenga C, Martinez Gache SA, Prevost JRC, Kozlova A, Spillier Q, Liberelle M, Benyahia Z, Messens J, Copetti T, Sonveaux P, Frederick R (2020) Interrogating the lactate dehydrogenase tetramerization site using (Stapled) peptides. J Med Chem 63:4628–4643. https://doi.org/10.1021/acs.jmedchem.9b01955
Thabault L, Liberelle M, Koruza K, Yildiz E, Joudiou N, Messens J, Brisson L, Wouters J, Sonveaux P, Frederick R (2021) Discovery of a novel lactate dehydrogenase tetramerization domain using epitope mapping and peptides. J Biol Chem 296:100422. https://doi.org/10.1016/j.jbc.2021.100422
Ullah MS, Davies AJ, Halestrap AP (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 281:9030–9037. https://doi.org/10.1074/jbc.M511397200
Urdang G (1942) Pictorial life history of the apothecary chemist Carl Wilhelm Scheele. American institute of the history of pharmacy, Wisconsin
Vadevoo SMP, Gunassekaran GR, Lee C, Lee N, Lee J, Chae S, Park JY, Koo J, Lee B (2021) The macrophage odorant receptor Olfr78 mediates the lactate-induced M2 phenotype of tumor-associated macrophages. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2102434118
Van Hee VF, Perez-Escuredo J, Cacace A, Copetti T, Sonveaux P (2015) Lactate does not activate NF-kappaB in oxidative tumor cells. Front Pharmacol 6:228. https://doi.org/10.3389/fphar.2015.00228
Van Hee VF, Labar D, Dehon G, Grasso D, Gregoire V, Muccioli GG, Frederick R, Sonveaux P (2017) Radiosynthesis and validation of (+/-)-[18F]-3-fluoro-2-hydroxypropionate ([18F]-FLac) as a PET tracer of lactate to monitor MCT1-dependent lactate uptake in tumors. Oncotarget 8:24415–24428. https://doi.org/10.18632/oncotarget.14705
Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033. https://doi.org/10.1126/science.1160809
Vanderlinde RE (1985) Measurement of total lactate dehydrogenase activity. Ann Clin Lab Sci 15:13–31
Vaupel P, Okunieff P, Neuringer LJ (1989) Blood flow, tissue oxygenation, pH distribution, and energy metabolism of murine mammary adenocarcinomas during growth. Adv Exp Med Biol 248:835–845. https://doi.org/10.1007/978-1-4684-5643-1_95
Vegran F, Boidot R, Michiels C, Sonveaux P, Feron O (2011) Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res 71:2550–2560. https://doi.org/10.1158/0008-5472.CAN-10-2828
Vlachostergios PJ, Oikonomou KG, Gibilaro E, Apergis G (2015) Elevated lactic acid is a negative prognostic factor in metastatic lung cancer. Cancer Biomark 15:725–734. https://doi.org/10.3233/CBM-150514
Voss DM, Spina R, Carter DL, Lim KS, Jeffery CJ, Bar EE (2017) Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression. Sci Rep 7:4292. https://doi.org/10.1038/s41598-017-04612-w
Wagner W, Ciszewski WM, Kania KD (2015) L- and D-lactate enhance DNA repair and modulate the resistance of cervical carcinoma cells to anticancer drugs via histone deacetylase inhibition and hydroxycarboxylic acid receptor 1 activation. Cell Commun Signal 13:36. https://doi.org/10.1186/s12964-015-0114-x
Wagner W, Kania KD, Blauz A, Ciszewski WM (2017a) The lactate receptor (HCAR1/GPR81) contributes to doxorubicin chemoresistance via ABCB1 transporter up-regulation in human cervical cancer HeLa cells. J Physiol Pharmacol 68:555–564
Wagner W, Kania KD, Ciszewski WM (2017b) Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity. DNA Repair (amst) 52:49–58. https://doi.org/10.1016/j.dnarep.2017.02.007
Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K, Rofstad EK, Mueller-Klieser W (2000) High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–921
Wang Y, Li X, Zhang L, Li M, Dai N, Luo H, Shan J, Yang X, Xu M, Feng Y, Xu C, Qian C, Wang D (2020) A randomized, double-blind, placebo-controlled study of B-cell lymphoma 2 homology 3 mimetic gossypol combined with docetaxel and cisplatin for advanced non-small cell lung cancer with high expression of apurinic/apyrimidinic endonuclease 1. Invest New Drugs 38:1862–1871. https://doi.org/10.1007/s10637-020-00927-0
Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, Lei J, Yan C (2021a) Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell 184:370-383 e313. https://doi.org/10.1016/j.cell.2020.11.043
Wang Y, Nie H, Liao Z, He X, Xu Z, Zhou J, Ou C (2021b) Expression and clinical significance of lactate dehydrogenase A in colon adenocarcinoma. Front Oncol 11:700795. https://doi.org/10.3389/fonc.2021.700795
Warburg O (1925) The metabolism of carcinoma cells. J Cancer Res 9:148–163. https://doi.org/10.1158/jcr.1925.148
Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM, Grebinoski S, Menk AV, Rittenhouse NL, Depeaux K, Whetstone RD, DaA V, Hand TW, Poholek AC, Morrison BM, Rothstein JD, Wendell SG, Delgoffe GM (2021) Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591:645–651. https://doi.org/10.1038/s41586-020-03045-2
Wei Y, Xu H, Dai J, Peng J, Wang W, Xia L, Zhou F (2018) Prognostic significance of serum lactic acid, lactate dehydrogenase, and albumin levels in patients with metastatic colorectal cancer. Biomed Res Int 2018:1804086. https://doi.org/10.1155/2018/1804086
Wu J, Hong Y, Wu T, Wang J, Chen X, Wang Z, Cheng B, Xia J (2018) Stromal-epithelial lactate shuttle induced by tumor-derived interleukin-1beta promotes cell proliferation in oral squamous cell carcinoma. Int J Mol Med 41:687–696. https://doi.org/10.3892/ijmm.2017.3267
Xia H, Wang W, Crespo J, Kryczek I, Li W, Wei S, Bian Z, Maj T, He M, Liu RJ, He Y, Rattan R, Munkarah A, Guan JL, Zou W (2017) Suppression of FIP200 and autophagy by tumor-derived lactate promotes naive T cell apoptosis and affects tumor immunity. Sci Immunol. https://doi.org/10.1126/sciimmunol.aan4631
Xie H, Hanai J, Ren JG, Kats L, Burgess K, Bhargava P, Signoretti S, Billiard J, Duffy KJ, Grant A, Wang X, Lorkiewicz PK, Schatzman S, Bousamra M 2nd, Lane AN, Higashi RM, Fan TW, Pandolfi PP, Sukhatme VP, Seth P (2014) Targeting lactate dehydrogenase–a inhibits tumorigenesis and tumor progression in mouse models of lung cancer and impacts tumor-initiating cells. Cell Metab 19:795–809. https://doi.org/10.1016/j.cmet.2014.03.003
Xie H, Yin J, Shah MH, Menefee ME, Bible KC, Reidy-Lagunes D, Kane MA, Quinn DI, Gandara DR, Erlichman C, Adjei AA (2019) A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma. Invest New Drugs 37:755–762. https://doi.org/10.1007/s10637-019-00797-1
Xie Q, Zhu Z, He Y, Zhang Z, Zhang Y, Wang Y, Luo J, Peng T, Cheng F, Gao J, Cao Y, Wei H, Wu Z (2020) A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells. Biochim Biophys Acta Mol Basis Dis 1866:165576. https://doi.org/10.1016/j.bbadis.2019.165576
Yang X, Lu Y, Hang J, Zhang J, Zhang T, Huo Y, Liu J, Lai S, Luo D, Wang L, Hua R, Lin Y (2020) Lactate-modulated immunosuppression of myeloid-derived suppressor cells contributes to the radioresistance of pancreatic cancer. Cancer Immunol Res 8:1440–1451. https://doi.org/10.1158/2326-6066.CIR-20-0111
Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, Locasale JW, Son J, Zhang H, Coloff JL, Yan H, Wang W, Chen S, Viale A, Zheng H, Paik JH, Lim C, Guimaraes AR, Martin ES, Chang J, Hezel AF, Perry SR, Hu J, Gan B, Xiao Y, Asara JM, Weissleder R, Wang YA, Chin L, Cantley LC, Depinho RA (2012) Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149:656–670. https://doi.org/10.1016/j.cell.2012.01.058
Ying M, You D, Zhu X, Cai L, Zeng S, Hu X (2021) Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions. Redox Biol 46:102065. https://doi.org/10.1016/j.redox.2021.102065
Yu M, Cui R, Huang Y, Luo Y, Qin S, Zhong M (2019) Increased proton-sensing receptor GPR4 signalling promotes colorectal cancer progression by activating the hippo pathway. EBioMedicine 48:264–276. https://doi.org/10.1016/j.ebiom.2019.09.016
Yu J, Chai P, Xie M, Ge S, Ruan J, Fan X, Jia R (2021) Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol 22:85. https://doi.org/10.1186/s13059-021-02308-z
Zdralevic M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking SM, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O’brien T, Oefner PJ, Renner K, Pouyssegur J, and Kreutz M, (2018a) Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism. J Biol Chem 293:15947–15961. https://doi.org/10.1074/jbc.RA118.004180
Zdralevic M, Vucetic M, Daher B, Marchiq I, Parks SK, Pouyssegur J (2018b) Disrupting the “Warburg effect” re-routes cancer cells to OXPHOS offering a vulnerability point via ’ferroptosis’-induced cell death. Adv Biol Regul 68:55–63. https://doi.org/10.1016/j.jbior.2017.12.002
Zhang D, Wang Y, Shi Z, Liu J, Sun P, Hou X, Zhang J, Zhao S, Zhou BP, Mi J (2015) Metabolic reprogramming of cancer-associated fibroblasts by IDH3alpha downregulation. Cell Rep 10:1335–1348. https://doi.org/10.1016/j.celrep.2015.02.006
Zhang D, Tang Z, Huang H, Zhou G, Cui C, Weng Y, Liu W, Kim S, Lee S, Perez-Neut M, Ding J, Czyz D, Hu R, Ye Z, He M, Zheng YG, Shuman HA, Dai L, Ren B, Roeder RG, Becker L, Zhao Y (2019a) Metabolic regulation of gene expression by histone lactylation. Nature 574:575–580. https://doi.org/10.1038/s41586-019-1678-1
Zhang W, Wang G, Xu ZG, Tu H, Hu F, Dai J, Chang Y, Chen Y, Lu Y, Zeng H, Cai Z, Han F, Xu C, Jin G, Sun L, Pan BS, Lai SW, Hsu CC, Xu J, Chen ZZ, Li HY, Seth P, Hu J, Zhang X, Li H, Lin HK (2019b) Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178:176-189 e115. https://doi.org/10.1016/j.cell.2019.05.003
Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z, Cai K, Zhao Y, Luo Z (2020) HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep 33:108487. https://doi.org/10.1016/j.celrep.2020.108487
Zhu D, Jiang Y, Cao H, Yang J, Shu Y, Feng H, Yang X, Sun X, Shao M (2022) Lactate: a regulator of immune microenvironment and a clinical prognosis indicator in colorectal cancer. Front Immunol 13:876195. https://doi.org/10.3389/fimmu.2022.876195
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This work was supported by a National Research Foundation of Korea (NRF) Grant funded by the Korea government (MSIT) (Grant No. NRF-2021R1C1C2003405).
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Byun, JK. Tumor lactic acid: a potential target for cancer therapy. Arch. Pharm. Res. 46, 90–110 (2023). https://doi.org/10.1007/s12272-023-01431-8
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DOI: https://doi.org/10.1007/s12272-023-01431-8