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. 1984 Apr;49(4):437–445. doi: 10.1038/bjc.1984.70

Hyperthermia, Na+K+ATPase and lactic acid production in some human tumour cells.

R H Burdon, S M Kerr, C M Cutmore, J Munro, V Gill
PMCID: PMC1976771  PMID: 6324839

Abstract

When HeLa cells are exposed to brief heat shock at 45 degrees C there is a reduction in the cellular level of Na+K+ATPase. Return of the cells to the normal growth temperature of 37 degrees C leads to a partial restoration of enzyme activity. The pattern of this recovery of activity suggests that it may be associated with the induction of heat shock proteins. Indeed other means of heat shock protein induction such as continuous heat treatment at 42 degrees C, or treatment of cells at 37 degrees C with sodium arsenite, leads to elevated levels of Na+K+ATPase activity and alterations in the kinetic properties of the enzyme. Continuous hyperthermia at 42 degrees C led to increased lactate production which could be blocked with ouabain suggesting that effects on Na+K+ATPase activity could partly influence glycolysis. A number of other human and hamster cells also showed increased lactate production at 42 degrees C and also an inhibition of lactate production by ouabain. Whilst incubation of HeLa cells with cyanide had little effect on glycolysis at 37 degrees C elevation of the temperature to 42 degrees C (or 45 degrees C), in the presence of cyanide, impaired glycolysis. The possible role in this phenomenon, of an unusual oxygen-sensitive isoenzyme of lactate dehydrogenase, expressed in human cancers, is discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson G. R., Kovacik W. P., Jr LDHk, an unusual oxygen-sensitive lactate dehydrogenase expressed in human cancer. Proc Natl Acad Sci U S A. 1981 May;78(5):3209–3213. doi: 10.1073/pnas.78.5.3209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Anderson G. R., Kovacik W. P., Jr, Marotti K. R. LDHk, a uniquely regulated cryptic lactate dehydrogenase associated with transformation by the Kirsten sarcoma virus. J Biol Chem. 1981 Oct 25;256(20):10583–10591. [PubMed] [Google Scholar]
  3. Anderson G. R., Marotti K. R., Whitaker-Dowling P. A. A candidate rat-specific gene product of the Kirsten murine sarcoma virus. Virology. 1979 Nov;99(1):31–48. doi: 10.1016/0042-6822(79)90034-5. [DOI] [PubMed] [Google Scholar]
  4. Anderson R. L., Minton K. W., Li G. C., Hahn G. M. Temperature-induced homeoviscous adaptation of Chinese hamster ovary cells. Biochim Biophys Acta. 1981 Mar 6;641(2):334–348. doi: 10.1016/0005-2736(81)90490-9. [DOI] [PubMed] [Google Scholar]
  5. BROADFOOT M., WALKER P., PAUL J., MACPHERSON I., STOKER M. GLYCOLYSIS AND RESPIRATION OF TRANSFORMED BHK21 CELLS. Nature. 1964 Oct 3;204:79–79. doi: 10.1038/204079a0. [DOI] [PubMed] [Google Scholar]
  6. Belt J. A., Thomas J. A., Buchsbaum R. N., Racker E. Inhibition of lactate transport and glycolysis in Ehrlich ascites tumor cells by bioflavonoids. Biochemistry. 1979 Aug 7;18(16):3506–3511. doi: 10.1021/bi00583a011. [DOI] [PubMed] [Google Scholar]
  7. Bonanou-Tzedaki S. A., Sohi M. K., Arnstein H. R. Regulation of protein synthesis in reticulocyte lysates. Characterization of the inhibitor generated in the postribosomal supernatant by heating at 44 degrees C. Eur J Biochem. 1981;114(1):69–77. [PubMed] [Google Scholar]
  8. Brotherus J. R., Jost P. C., Griffith O. H., Keana J. F., Hokin L. E. Charge selectivity at the lipid-protein interface of membranous Na,K-ATPase. Proc Natl Acad Sci U S A. 1980 Jan;77(1):272–276. doi: 10.1073/pnas.77.1.272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Burdon R. H., Cutmore C. M. Human heat shock gene expression and the modulation of plasma membrane Na+, K+-ATPase activity. FEBS Lett. 1982 Apr 5;140(1):45–48. doi: 10.1016/0014-5793(82)80517-6. [DOI] [PubMed] [Google Scholar]
  10. Burdon R. H., Slater A., McMahon M., Cato A. C. Hyperthermia and the heat-shock proteins of HeLa cells. Br J Cancer. 1982 Jun;45(6):953–963. doi: 10.1038/bjc.1982.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Carafoli E. Mitochondrial uptake of calcium ions and the regulation of cell function. Biochem Soc Symp. 1974;(39):89–109. [PubMed] [Google Scholar]
  12. Cato A. C., Adams R. L., Burdon R. H. Genome modification in two lines of baby hamster kidney fibroblasts (BHK-21). Biochim Biophys Acta. 1978 Nov 21;521(1):397–406. doi: 10.1016/0005-2787(78)90281-2. [DOI] [PubMed] [Google Scholar]
  13. Cooper J. A., Reiss N. A., Schwartz R. J., Hunter T. Three glycolytic enzymes are phosphorylated at tyrosine in cells transformed by Rous sarcoma virus. Nature. 1983 Mar 17;302(5905):218–223. doi: 10.1038/302218a0. [DOI] [PubMed] [Google Scholar]
  14. Cress A. E., Gerner E. W. Cholesterol levels inversely reflect the thermal sensitivity of mammalian cells in culture. Nature. 1980 Feb 14;283(5748):677–679. doi: 10.1038/283677a0. [DOI] [PubMed] [Google Scholar]
  15. DRAHOTA Z., CARAFOLI E., ROSSI C. S., GAMBLE R. L., LEHNINGER A. L. THE STEADY STATE MAINTENANCE OF ACCUMULATED CA++ IN RAT LIVER MITOCHONDRIA. J Biol Chem. 1965 Jun;240:2712–2720. [PubMed] [Google Scholar]
  16. Edidin M. Rotational and translational diffusion in membranes. Annu Rev Biophys Bioeng. 1974;3(0):179–201. doi: 10.1146/annurev.bb.03.060174.001143. [DOI] [PubMed] [Google Scholar]
  17. Field S. B., Anderson R. L. Thermotolerance: a review of observations and possible mechanisms. Natl Cancer Inst Monogr. 1982 Jun;61:193–201. [PubMed] [Google Scholar]
  18. Field S. B., Bleehen N. M. Hyperthermia in the treatment of cancer. Cancer Treat Rev. 1979 Jun;6(2):63–94. doi: 10.1016/s0305-7372(79)80043-2. [DOI] [PubMed] [Google Scholar]
  19. Gerweck L. E., Jennings M., Richards B. Influence of pH on the response of cells to single and split doses of hyperthermia. Cancer Res. 1980 Nov;40(11):4019–4024. [PubMed] [Google Scholar]
  20. Gerweck L. E. Modification of cell lethality at elevated temperatures. The pH effect. Radiat Res. 1977 Apr;70(1):224–235. [PubMed] [Google Scholar]
  21. Gullino P. M., Grantham F. H., Smith S. H., Haggerty A. C. Modifications of the acid-base status of the internal milieu of tumors. J Natl Cancer Inst. 1965 Jun;34(6):857–869. [PubMed] [Google Scholar]
  22. Hazel J. R., Prosser C. L. Molecular mechanisms of temperature compensation in poikilotherms. Physiol Rev. 1974 Jul;54(3):620–677. doi: 10.1152/physrev.1974.54.3.620. [DOI] [PubMed] [Google Scholar]
  23. Henle K. J., Karamuz J. E., Leeper D. B. Induction of thermotolerance in Chinese hamster ovary cells by high (45 degrees) or low (40 degrees) hyperthermia. Cancer Res. 1978 Mar;38(3):570–574. [PubMed] [Google Scholar]
  24. Hickey E. D., Weber L. A. Modulation of heat-shock polypeptide synthesis in HeLa cells during hyperthermia and recovery. Biochemistry. 1982 Mar 30;21(7):1513–1521. doi: 10.1021/bi00536a008. [DOI] [PubMed] [Google Scholar]
  25. Hughes E. N., August J. T. Coprecipitation of heat shock proteins with a cell surface glycoprotein. Proc Natl Acad Sci U S A. 1982 Apr;79(7):2305–2309. doi: 10.1073/pnas.79.7.2305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Johnsen S., Stokke T., Prydz H. HeLa cell plasma membranes. I. 5'-Nucleotidase and ouabain-sensitive ATPase as markers for plasma membranes. J Cell Biol. 1974 Nov;63(2 Pt 1):357–363. doi: 10.1083/jcb.63.2.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li G. C., Werb Z. Correlation between synthesis of heat shock proteins and development of thermotolerance in Chinese hamster fibroblasts. Proc Natl Acad Sci U S A. 1982 May;79(10):3218–3222. doi: 10.1073/pnas.79.10.3218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lunec J., Cresswell S. R. Heat-induced thermotolerance expressed in the energy metabolism of mammalian cells. Radiat Res. 1983 Mar;93(3):588–597. [PubMed] [Google Scholar]
  29. McDonough J. P., Mahler H. P. Covalent phosphorylation of the Mg2+-dependent ATPase of yeast plasma membranes. J Biol Chem. 1982 Dec 25;257(24):14579–14581. [PubMed] [Google Scholar]
  30. Meli J., Bygrave F. L. The role of mitochondria in modifying calcium-sensitive cytoplasmic metabolic activities. Modification of pyruvate kinase activity. Biochem J. 1972 Jun;128(2):415–420. doi: 10.1042/bj1280415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. NAESLUND J., SWENSON K. E. Investigations on the pH of malignant tumors in mice and humans after the administration of glucose. Acta Obstet Gynecol Scand. 1953;32(3):359–367. doi: 10.3109/00016345309157588. [DOI] [PubMed] [Google Scholar]
  32. Overgaard J., Bichel P. The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitro. Radiology. 1977 May;123(2):511–514. doi: 10.1148/123.2.511. [DOI] [PubMed] [Google Scholar]
  33. Pouysségur J., Franchi A., Salomon J. C., Silvestre P. Isolation of a Chinese hamster fibroblast mutant defective in hexose transport and aerobic glycolysis: its use to dissect the malignant phenotype. Proc Natl Acad Sci U S A. 1980 May;77(5):2698–2701. doi: 10.1073/pnas.77.5.2698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Racker E., Johnson J. H., Blackwell M. T. The role of ATPase in glycolysis of Ehrlich ascites tumor cells. J Biol Chem. 1983 Mar 25;258(6):3702–3705. [PubMed] [Google Scholar]
  35. Rattray J. B., Schibeci A., Kidby D. K. Lipids of yeasts. Bacteriol Rev. 1975 Sep;39(3):197–231. doi: 10.1128/br.39.3.197-231.1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Scholnick P., Lang D., Racker E. Regulatory mechanisms in carbohydrate metabolism. IX. Stimulation of aerobic glycolysis by energy-linked ion transport and inhibition by dextran sulfate. J Biol Chem. 1973 Jul 25;248(14):5175–5175. [PubMed] [Google Scholar]
  37. Singh M., Singh V. N., August J. T., Horecker B. L. Alterations in glucose metabolism in chick embryo cells transformed by Rous sarcoma virus. Transformation-specific changes in the activities of key enzymes of the glycolytic and hexose monophosphate shunt pathways. Arch Biochem Biophys. 1974 Nov;165(1):240–246. doi: 10.1016/0003-9861(74)90160-x. [DOI] [PubMed] [Google Scholar]
  38. Strobel G. A. The relationship between membrane ATPase activity in sugarcane and heat-induced resistance to helminthosporoside. Biochim Biophys Acta. 1979 Jul 5;554(2):460–468. doi: 10.1016/0005-2736(79)90384-5. [DOI] [PubMed] [Google Scholar]
  39. Suolinna E. M., Lang D. R., Racker E. Quercetin, an artificial regulator of the high aerobic glycolysis of tumor cells. J Natl Cancer Inst. 1974 Nov;53(5):1515–1519. doi: 10.1093/jnci/53.5.1515. [DOI] [PubMed] [Google Scholar]
  40. Tanaka R., Teruya A. Lipid dependence of activity-temperature relationship of (Na+, K+)-activated ATPase. Biochim Biophys Acta. 1973 Nov 16;323(4):584–591. doi: 10.1016/0005-2736(73)90166-1. [DOI] [PubMed] [Google Scholar]
  41. Wang C., Asai D. J., Lazarides E. The 68,000-dalton neurofilament-associated polypeptide is a component of nonneuronal cells and of skeletal myofibrils. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1541–1545. doi: 10.1073/pnas.77.3.1541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Wang C., Gomer R. H., Lazarides E. Heat shock proteins are methylated in avian and mammalian cells. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3531–3535. doi: 10.1073/pnas.78.6.3531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Yeh L. A., Ling L., English L., Cantley L. Phosphorylation of the (Na,K)-ATPase by a plasma membrane-bound protein kinase in friend erythroleukemia cells. J Biol Chem. 1983 May 25;258(10):6567–6574. [PubMed] [Google Scholar]

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