User menu

Accès à distance ? S'identifier sur le proxy UCLouvain

Lactate does not activate NF-κB in oxidative tumor cells.

Primary tabs

download
  • Open access
  • PDF
  • 4.65 M
Van Hee, Vincent [UCL] Perez Escuredo, Jhudit [UCL] Cacace, Andrea [UCL] Copetti, Tamara [UCL] Sonveaux, Pierre [UCL]

The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis. These protumoral activities of lactate depend on lactate uptake, a process primarily facilitated by the inward, passive lactate-proton symporter monocarboxylate transporter 1 (MCT1); the conversion of lactate and NAD(+) to pyruvate, NADH and H(+) by lactate dehydrogenase-1 (LDH-1); and a competition between pyruvate and α-ketoglutarate that inhibits prolylhydroxylases (PHDs). Endothelial cells do not primarily use lactate as an oxidative fuel but, rather, as a signaling agent. In addition to HIF-1, lactate can indeed activate transcription factor nuclear factor-κB (NF-κB) in these cells, through a mechanism not only depending on PHD inhibition but also on NADH alimenting NAD(P)H oxidases to generate reactive oxygen species (ROS). While NF-κB activity in endothelial cells promotes angiogenesis, NF-κB activation in tumor cells is known to stimulate tumor progression by conferring resistance to apoptosis, stemness, pro-angiogenic and metastatic capabilities. In this study, we therefore tested whether exogenous lactate could activate NF-κB in oxidative tumor cells equipped for lactate signaling. We report that, precisely because they are oxidative, HeLa and SiHa human tumor cells do not activate NF-κB in response to lactate. Indeed, while lactate-derived pyruvate is well-known to inhibit PHDs in these cells, we found that NADH aliments oxidative phosphorylation (OXPHOS) in mitochondria rather than NAD(P)H oxidases in the cytosol. These data were confirmed using oxidative human Cal27 and MCF7 tumor cells. This new information positions the malate-aspartate shuttle as a key player in the oxidative metabolism of lactate: similar to glycolysis that aliments OXPHOS with pyruvate produced by pyruvate kinase and NADH produced by glyceraldehyde-3-phosphate dehydrogenase (GAPDH), oxidative lactate metabolism aliments OXPHOS in oxidative tumor cells with pyruvate and NADH produced by LDH1.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2015
Language Anglais
Journal information "Frontiers in Pharmacology" - Vol. 6, p. 228 (2015)
Peer reviewed yes
Publisher Frontiers Research Foundation
issn 1663-9812
e-issn 1663-9812
Publication status Publié
Affiliations UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
UCL - SSS/IREC - Institut de recherche expérimentale et clinique
Links
  1. Chaturvedi M M, Sung B, Yadav V R, Kannappan R, Aggarwal B B, NF-κB addiction and its role in cancer: ‘one size does not fit all’, 10.1038/onc.2010.566
  2. Chereddy Kiran Kumar, Her Charles-Henry, Comune Michela, Moia Claudia, Lopes Alessandra, Porporato Paolo E., Vanacker Julie, Lam Martin C., Steinstraesser Lars, Sonveaux Pierre, Zhu Huijun, Ferreira Lino S., Vandermeulen Gaëlle, Préat Véronique, PLGA nanoparticles loaded with host defense peptide LL37 promote wound healing, 10.1016/j.jconrel.2014.08.016
  3. Chereddy Kiran Kumar, Lopes Alessandra, Koussoroplis Salome, Payen Valéry, Moia Claudia, Zhu Huijun, Sonveaux Pierre, Carmeliet Peter, des Rieux Anne, Vandermeulen Gaëlle, Préat Véronique, Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds, 10.1016/j.nano.2015.07.006
  4. Chu Wen-Ming, Tumor necrosis factor, 10.1016/j.canlet.2012.10.014
  5. Colegio Oscar R., Chu Ngoc-Quynh, Szabo Alison L., Chu Thach, Rhebergen Anne Marie, Jairam Vikram, Cyrus Nika, Brokowski Carolyn E., Eisenbarth Stephanie C., Phillips Gillian M., Cline Gary W., Phillips Andrew J., Medzhitov Ruslan, Functional polarization of tumour-associated macrophages by tumour-derived lactic acid, 10.1038/nature13490
  6. De Bock Katrien, Georgiadou Maria, Carmeliet Peter, Role of Endothelial Cell Metabolism in Vessel Sprouting, 10.1016/j.cmet.2013.08.001
  7. De Saedeleer Christophe J., Copetti Tamara, Porporato Paolo E., Verrax Julien, Feron Olivier, Sonveaux Pierre, Lactate Activates HIF-1 in Oxidative but Not in Warburg-Phenotype Human Tumor Cells, 10.1371/journal.pone.0046571
  8. De Saedeleer C J, Porporato P E, Copetti T, Pérez-Escuredo J, Payen V L, Brisson L, Feron O, Sonveaux P, Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration, 10.1038/onc.2013.454
  9. Dhup Suveera, Kumar Dadhich Rajesh, Ettore Porporato Paolo, Sonveaux Pierre, Multiple Biological Activities of Lactic Acid in Cancer: Influences on Tumor Growth,Angiogenesis and Metastasis, 10.2174/138161212799504902
  10. DIMMER Kai-Stefan, FRIEDRICH Björn, LANG Florian, DEITMER Joachim W., BRÖER Stefan, The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells, 10.1042/bj3500219
  11. Dionisi O., Longhi G., Eboli M.L., Galeotti T., Terranova T., Oxidation of reduced nicotinamide-adenine dinucleotide by the malate—Aspartate shuttle in Ehrlich ascites tumour cells, 10.1016/0005-2728(74)90142-x
  12. Gloire Geoffrey, Legrand-Poels Sylvie, Piette Jacques, NF-κB activation by reactive oxygen species: Fifteen years later, 10.1016/j.bcp.2006.04.011
  13. Greenhouse, Cancer Res., 37, 4173 (1977)
  14. Guillaumond F., Leca J., Olivares O., Lavaut M.-N., Vidal N., Berthezene P., Dusetti N. J., Loncle C., Calvo E., Turrini O., Iovanna J. L., Tomasini R., Vasseur S., Strengthened glycolysis under hypoxia supports tumor symbiosis and hexosamine biosynthesis in pancreatic adenocarcinoma, 10.1073/pnas.1219555110
  15. Halestrap Andrew P., Wilson Marieangela C., The monocarboxylate transporter family-Role and regulation, 10.1002/iub.572
  16. Kennedy Kelly M, Dewhirst Mark W, Tumor metabolism of lactate: the influence and therapeutic potential for MCT and CD147 regulation, 10.2217/fon.09.145
  17. Kennedy Kelly M., Scarbrough Peter M., Ribeiro Anthony, Richardson Rachel, Yuan Hong, Sonveaux Pierre, Landon Chelsea D., Chi Jen-Tsan, Pizzo Salvatore, Schroeder Thies, Dewhirst Mark W., Catabolism of Exogenous Lactate Reveals It as a Legitimate Metabolic Substrate in Breast Cancer, 10.1371/journal.pone.0075154
  18. Lu Huasheng, Dalgard Clifton L., Mohyeldin Ahmed, McFate Thomas, Tait A. Sasha, Verma Ajay, Reversible Inactivation of HIF-1 Prolyl Hydroxylases Allows Cell Metabolism to Control Basal HIF-1, 10.1074/jbc.m508718200
  19. Lu Huasheng, Forbes Robert A., Verma Ajay, Hypoxia-inducible Factor 1 Activation by Aerobic Glycolysis Implicates the Warburg Effect in Carcinogenesis, 10.1074/jbc.m202487200
  20. Mendoza-Juez Berta, Martínez-González Alicia, Calvo Gabriel F., Pérez-García Víctor M., A Mathematical Model for the Glucose-Lactate Metabolism of in Vitro Cancer Cells, 10.1007/s11538-011-9711-z
  21. Muntané Jordi, Harnessing Tumor Necrosis Factor Receptors to Enhance Antitumor Activities of Drugs, 10.1021/tx2002349
  22. Payen Valéry L., Brisson Lucie, Dewhirst Mark W., Sonveaux Pierre, Common Responses of Tumors and Wounds to Hypoxia : , 10.1097/ppo.0000000000000098
  23. Porporato Paolo E., Dhup Suveera, Dadhich Rajesh K., Copetti Tamara, Sonveaux Pierre, Anticancer Targets in the Glycolytic Metabolism of Tumors: A Comprehensive Review, 10.3389/fphar.2011.00049
  24. Porporato Paolo E., Payen Valéry L., De Saedeleer Christophe J., Préat Véronique, Thissen Jean-Paul, Feron Olivier, Sonveaux Pierre, Lactate stimulates angiogenesis and accelerates the healing of superficial and ischemic wounds in mice, 10.1007/s10456-012-9282-0
  25. Samartsev Victor N, Smirnov Anatoliy V, Zeldi Ivan P, Markova Olga V, Mokhova Elena N, Skulachev Vladimir P, Involvement of aspartate/glutamate antiporter in fatty acid-induced uncoupling of liver mitochondria, 10.1016/s0005-2728(96)00166-1
  26. Sonveaux Pierre, Copetti Tamara, De Saedeleer Christophe J., Végran Frédérique, Verrax Julien, Kennedy Kelly M., Moon Eui Jung, Dhup Suveera, Danhier Pierre, Frérart Françoise, Gallez Bernard, Ribeiro Anthony, Michiels Carine, Dewhirst Mark W., Feron Olivier, Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis, 10.1371/journal.pone.0033418
  27. Sonveaux Pierre, Végran Frédérique, Schroeder Thies, Wergin Melanie C., Verrax Julien, Rabbani Zahid N., De Saedeleer Christophe J., Kennedy Kelly M., Diepart Caroline, Jordan Bénédicte F., Kelley Michael J., Gallez Bernard, Wahl Miriam L., Feron Olivier, Dewhirst Mark W., Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice, 10.1172/jci36843
  28. Ullah Mohammed S., Davies Andrew J., Halestrap Andrew P., The Plasma Membrane Lactate Transporter MCT4, but Not MCT1, Is Up-regulated by Hypoxia through a HIF-1α-dependent Mechanism, 10.1074/jbc.m511397200
  29. Buul J.D. Van, Fernandez-Borja M., Anthony E.C., Hordijk P.L., Expression and Localization of NOX2 and NOX4 in Primary Human Endothelial Cells, 10.1089/ars.2005.7.308
  30. Vander Heiden M. G., Cantley L. C., Thompson C. B., Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation, 10.1126/science.1160809
  31. Vegran F., Boidot R., Michiels C., Sonveaux P., Feron O., Lactate Influx through the Endothelial Cell Monocarboxylate Transporter MCT1 Supports an NF- B/IL-8 Pathway that Drives Tumor Angiogenesis, 10.1158/0008-5472.can-10-2828
  32. Vegran F., Seront E., Sonveaux P., Feron O., Lactate-Induced IL-8 Pathway in Endothelial Cells--Response, 10.1158/0008-5472.can-12-0012
  33. Viatour Patrick, Merville Marie-Paule, Bours Vincent, Chariot Alain, Phosphorylation of NF-κB and IκB proteins: implications in cancer and inflammation, 10.1016/j.tibs.2004.11.009
  34. Walenta Stefan, Mueller-Klieser Wolfgang F, Lactate: mirror and motor of tumor malignancy, 10.1016/j.semradonc.2004.04.004
  35. Whitaker-Menezes Diana, Martinez-Outschoorn Ubaldo E., Lin Zhao, Ertel Adam, Flomenberg Neal, Witkiewicz Agnieszka K., Birbe Ruth, Howell Anthony, Pavlides Stephanos, Gandara Ricardo, Pestell Richard G., Sotgia Federica, Philp Nancy J., Lisanti Michael P, Evidence for a stromal-epithelial “lactate shuttle” in human tumors : MCT4 is a marker of oxidative stress in cancer-associated fibroblasts, 10.4161/cc.10.11.15659
  36. Ying Weihai, NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences, 10.1089/ars.2007.1672
  37. Yuan Yu-he, Sun Jian-dong, Wu Miao-miao, Hu Jin-feng, Peng Shan-ying, Chen Nai-Hong, Rotenone Could Activate Microglia Through NFκB Associated Pathway, 10.1007/s11064-013-1055-7
Bibliographic reference Van Hee, Vincent ; Perez Escuredo, Jhudit ; Cacace, Andrea ; Copetti, Tamara ; Sonveaux, Pierre. Lactate does not activate NF-κB in oxidative tumor cells.. In: Frontiers in Pharmacology, Vol. 6, p. 228 (2015)
Permanent URL http://hdl.handle.net/2078.1/167748