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Modeling of pH regulation in tumor cells: Direct interaction between proton-coupled lactate transporters and cancer-associated carbonicanhydrase

1 Technische Universität Kaiserslautern (TUK) Felix-Klein-Zentrum für Mathematik Paul-Ehrlich-Str. 31, 67663 Kaiserslautern, Germany
2 Technische Universität Kaiserslautern (TUK), Division of General Zoology, Department of Biology, Erwin-Schrödinger-Str. 13, 67663 Kaiserslautern, Germany
3 University of Veterinary Medicine Hannover, Institute of Physiological Chemistry, Bünteweg 17, 30559 Hannover, Germany

The most aggressive tumor cells, which often reside in a hypoxic environment, can release vast amounts of lactate and protons via monocarboxylate transporters (MCTs). This additional proton efflux exacerbates extracellular acidification and supports the formation of a hostile environment. In the present study we propose a novel, data-based model for this proton-coupled lactate transport in cancer cells. The mathematical settings involve systems coupling nonlinear ordinary and stochastic differential equations describing the dynamics of intra- and extracellular proton and lactate concentrations. The data involve time series of intracellular proton concentrations of normoxic and hypoxic MCF-7 breast cancer cells. The good agreement of our final model with the data suggests the existence of proton pools near the cell membrane, which can be controlled by intracellular and extracellular carbonic anhydrases to drive proton-coupled lactate transport across the plasma membrane of hypoxic cancer cells.
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Keywords dynamic buffer capacity; two-compartment model; stochastic differential equations; numerical simulations

Citation: Sandesh Athni Hiremath, Christina Surulescu, Somayeh Jamali, Samantha Ames, Joachim W. Deitmer, Holger M. Becker. Modeling of pH regulation in tumor cells: Direct interaction between proton-coupled lactate transporters and cancer-associated carbonicanhydrase. Mathematical Biosciences and Engineering, 2019, 16(1): 320-337. doi: 10.3934/mbe.2019016


  • 1. J. Almquist, P. Lang, D. Prätzel-Wolters, J. W. Deitmer, M. Jirstrand and H. M. Becker, A Kinetic Model of the Monocarboxylate Transporter MCT1 and its Interaction with Carbonic Anhydrase II, J. Comp. Sci. Sys. Biol., 3 (2010), 107–116.
  • 2. S. Ames, S. Pastorekova and H. M. Becker, The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells, Oncotarget, 9 (2018), 27940–27957.
  • 3. H. M. Becker and J. W. Deitmer, Nonenzymatic proton handling by carbonic anhydrase II during H+-lactate cotransport via monocarboxylate transporter 1, J. Biol. Chem., 283 (2008), 21655– 21667.
  • 4. H. M. Becker, D. Hirnet, C. Fecher-Trost, D. Sültemeyer and J. W. Deitmer, Transport activity of MCT1 expressed in Xenopus oocytes is increased by interaction with carbonic anhydrase, J. Biol. Chem., 280 (2005), 39882–39889.
  • 5. H. M. Becker, M. Klier and J. W. Deitmer, Nonenzymatic augmentation of lactate transport via monocarboxylate transporter isoform 4 by carbonic anhydrase II, J. Membrane Biol., 234 (2010), 125–135.
  • 6. H. M. Becker, M. Klier, C. Schüler, R. McKenna and J. W. Deitmer, Intramolecular proton shuttle supports not only catalytic but also noncatalytic function of carbonic anhydrase II, P. Natl. Acad. Sci. USA., 108 (2011), 3071–3076.
  • 7. M. C. Brahimi-Horn, G. Bellot and J. Pouysségur, Hypoxia and energetic tumour metabolism, Curr. Opin. Genet. Dev., 21 (2011), 67–72.
  • 8. R. A. Cardone, V. Casavola and S. J. Reshkin, The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis, Nat. Rev. Cancer, 5 (2005), 786–795.
  • 9. A. W. De Bruijne, H. Vreeburg and J. Van Steveninck, Kinetic analysis of L-lactate transport in human erythrocytes via the monocarboxylate-specific carrier system, Biochim. Biophys. Acta., 732 (1983), 562–568.
  • 10. R. A. Gatenby and R. J. Gillies, Why do cancers have high aerobic glycolysis? Nat. Rev. Cancer, 4 (2004), 891–899.
  • 11. A. P. Halestrap and N. T. Price, The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation Biochem. J., 343 (1999), 281–299.
  • 12. D. Hanahan and R. A. Weinberg, Hallmarks of cancer: the next generation, Cell, 144 (2011), 646–674.
  • 13. S. A. Hiremath, Multiscale modeling of acid mediated cancer invasion with random dynamics and beyond, Ph.D thesis, University of Kaiserslautern (TUK), 2017.
  • 14. S. A. Hiremath, S. Sonner, C. Surulescu and A. Zhigun, On a coupled SDE-PDE system modeling acid-mediated tumor invasion, Discrete. Cont. Dyn.-B , 23 (2018), 2339–2369.
  • 15. S. A. Hiremath and C. Surulescu, A stochastic multiscale model for acid mediated cancer invasion, Nonlinear. Anal., 22 (2015), 176–205.
  • 16. S. A. Hiremath and C. Surulescu, A stochastic model featuring acid-induced gaps during tumor progression, Nonlinearity, 29 (2016), 851–914.
  • 17. A. Innocenti, S. Pastorekova, J. Pastorek, A. Scozzafava, G. De Simone and C. T. Supuran, The proteoglycan region of the tumor-associated carbonic anhydrase isoform IX acts as anintrinsic buffer optimizing CO2 hydration at acidic pH values characteristic of solid tumors, Bioorg. Med. Chem. Lett., 19 (2009), 5825–5828.
  • 18. M. Irving, J. Maylie, L. N. Sizto and K. W. Chandler, Intracellular diffusion in the presence of mobile buffers. Application to proton movement in muscle, Biophys. J., 57 (1990), 717–721.
  • 19. S. Jamali, M. Klier, S. Ames, L. F. Barros, R. McKenna, J.W. Deitmer and H. M. Becker, Hypoxiainduced carbonic anhydrase IX facilitates lactate flux in human breast cancer cells by non-catalytic function, Sci. Rep., 5 (2015), 13605.
  • 20. C. Juel A. P. and Halestrap, Lactate transport in skeletal muscle - role and regulation of the monocarboxylate transporter, J. Physiol., 517 (1999), 633–642.
  • 21. P. E. Kloeden, S. Sonner and C. Surulescu, A nonlocal sample dependence SDE-PDE system modeling proton dynamics in a tumor, Discrete. Cont. Dyn.-B , 21 (2016), 2233–2254.
  • 22. A. H. Lee and I. F. Tannock, Heterogeneity of intracellular pH and of mechanisms that regulate intracellular pH in populations of cultured cells, Cancer. Res., 58 (1998), 1901–1908.
  • 23. C. Martin, S. F. Pedersen, A. Schwab and C. Stock, Intracellular pH gradients in migrating cells, Am. J. Physiol. Cell. Physiol., 300 (2011), C490–495.
  • 24. C. Martinez, D. Kalise and L. F. Barros, General Requirement for Harvesting Antennae at Ca(2+) and H(+) Channels and Transporters, Front. Neuroenergetics, 2 (2010), 27.
  • 25. P. E. Morgan, S. Pastorekova, A. K. Stuart-Tilley, S. L. Alper and J.R. Casey, Interactions of transmembrane carbonic anhydrase, CAIX, with bicarbonate transporters, Am. J. Physiol. Cell. Physiol., 293 (2007), C738–748.
  • 26. S. I. Noor, S. Dietz, H. Heidtmann, C. D. Boone, R. McKenna, J. W. Deitmer and H.M. Becker, Analysis of the Binding Moiety Mediating the Interaction between Monocarboxylate Transporters and Carbonic Anhydrase II, J. Biol. Chem., 290 (2015), 4476–4486.
  • 27. S. I. Noor, S. Jamali, S. Ames, S. Langer, J. W. Deitmer and H. M. Becker, A surface proton antenna in carbonic anhydrase II supports lactate transport in cancer cells, eLife 7 (2018), 1–31.
  • 28. S. K. Parks, J. Chiche and J. Pouyssegur, pH control mechanisms of tumor survival and growth, J. Cell. Physiol., 226 (2011), 299–308.
  • 29. S. K. Parks, J. Chiche and J. Pouyssegur, Disrupting proton dynamics and energy metabolism for cancer therapy, Nat. Rev. Cancer., 13 (2013), 611–623.
  • 30. R. C. Poole and A. P. Halestrap, Transport of lactate and other monocarboxylates across mammalian plasma membranes, Am. J. Physiol., 264 (1993), C761–782.
  • 31. P. E. Porporato, S. Dhup, R. K. Dadhich, T. Copetti and P. Sonveaux, Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review, Front. Pharmacol., 2 (2011), 49.
  • 32. A. Roos and W. F. Boron, Intracellular pH, Physiol. Rev., 61 (1981), 296–434.
  • 33. A. Schulze and A. L. Harris, How cancer metabolism is tuned for proliferation and vulnerable to disruption, Nature, 491 (2012), 364–373.
  • 34. O. Sedlakova, E. Svastova, M. Takacova, J. Kopacek, J. Pastorek and S. Pastorekova, Carbonic anhydrase IX, a hypoxia-induced catalytic component of the pH regulating machinery in tumors, Front. Physiol., 4 (2014), 400.
  • 35. C. Stock and A. Schwab, Protons make tumor cells move like clockwork, Pflügers Archiv : European journal of physiology, 458 (2009), 981–992.
  • 36. M. H. Stridh, M. D. Alt, S. Wittmann, H. Heidtmann, M. Aggarwal, B. Riederer, U. Seidler, G. Wennemuth, R. McKenna, J. W. Deitmer and H.M. Becker, Lactate flux in astrocytes is enhanced by a non-catalytic action of carbonic anhydrase II, J. Physiol., 590 (2012), 2333–2351.
  • 37. E. Svastova, W. Witarski, L. Csaderova, T. Kosik, L. Skvarkova, A. Hulikova, M. Zatovicova, M. Barathova, J. Kopacek, J. Pastorek and S. Pastorekova, Carbonic anhydrase IX interacts with bicarbonate transporters in lamellipodia and increases cell migration via its catalytic domain, J. Biol. Chem., 287 (2012), 3392–3402.
  • 38. P. Swietach, A. Hulikova, R. D. Vaughan-Jones and A.L. Harris, New insights into the physiological role of carbonic anhydrase IX in tumour pH regulation, Oncogene, 29 (2010), 6509– 6521.
  • 39. P. Swietach, R. D. Vaughan-Jones, A. L. Harris and A. Hulikova, The chemistry, physiology and pathology of pH in cancer, Philosophical Transactions of the Royal Society of London. Series B, Biological sciences, 369 (2014), 20130099.
  • 40. M. S. Ullah, A. J. Davies and A. P. Halestrap, The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism, J. Biol. Chem., 281 (2006), 9030–9037.
  • 41. O. Warburg, F. Wind and E. Negelein, The metabolism of tumors in the body, J. Gen. Physiol., 8 (1927), 519–530.
  • 42. S. Weinhouse, O. Warburg, D. Burk and A. L. Schade, On respiratory impairment in cancer cells, Science, 124 (1956), 269–270.


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