Expression of cysteine-containing low molecular weight proteins - metallothioneins and activity of cysteine protease - caspase-3 in lymphocytes of patients with chronic B-lymphocytic leukemia were evaluated before and after modification of their redox status. An increased caspase-3 activity was detected in lymphocytes of patients with B-CLL compared to normal cells under physiological condition. H2O2-induced oxidative stress in leukemic cells led to the activation of caspase-dependent apoptotic processes. It has been established that metallothioneins are the main triggers in this process. These polypeptides can deposit zinc ions and thereby play a significant role in process mediated by cell zinc signaling under chronic B-lymphocytic leukemia.
chronic B-lymphocytic leukemia, metallothioneins, caspase-3, redox-state, zinc homeostasis
1. Haq F., Mahoney M., Koropatnick J. Signaling events for metallothionein induction. Mutat. Res., 2003, vol. 533, no. 1-2. DOI:https://doi.org/10.1016/j.mrfmmm.2003.07.014.
2. Garmaza Yu.M., Tamashevskiy A.V., Slobozhanina E.I. Metallotioneiny mlekopitayuschih: struktura i biologicheskaya rol'. Izvestiya NAN Belarusi. Seriya biologicheskih nauk, 2016, № 1, s. 107-116. @@[Harmaza Y.M., Tamashevski A.V., Slobozhanina E.I. Mammalian methalothioneins: structure and biological role. Proceedings of the National academy of sciences of Belarus, 2016, no. 1, pp. 107-116 (In Russ)]
3. Dutsch-Wicherek M., Sikora J., Tomaszewska R. The possible biological role of metallothionein in apoptosis. Frontiers in Bioscience, 2008, no. 13. DOI:https://doi.org/10.2741/2991.
4. Wang G.W., Klein J.B., Kang Y.J. Metallothionein inhibits doxorubicin-induced mitochondrial cytochrome c release and caspase-3 activation in cardiomyocytes. Journal of Pharmacology and Experimental Therapeutics, 2001, vol. 298, no. 2, pp. 461-468. DOI: 0022-3565/01/2982-461-468.
5. Kang Y.J., Zhou Z.X., Wang G.W., Buridi A., Klein J.B. Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases. Journal of Biological Chemistry, 2000, vol. 275, no. 18. DOI:https://doi.org/10.1074/jbc.275.18.13690.
6. Pan G., Humke E.W., Dixit V.M. Activation of caspases triggered by cytochrome c in vitro. FEBS Letters, 1998, vol. 426, no. 1. DOI:https://doi.org/10.1016/s0014-5793(98)00330-5.
7. Ma Y., Ogino T., Kawabata T., Li J., Eguchi K., Okada S. Cupric nitrilotriacetate-induced apoptosis in HL-60 cells association with lipid peroxidation, release of cytochrome C from mitochondria, and activation of caspase-3. Free Radical Biology & Medicine, 1999, vol.27, no. 1-2. DOI:https://doi.org/10.1016/S0891-5849(99)00083-0.
8. Wu H., Che X., Zheng Q., Wu A., Pan K., Shao A., Wu Q., Zhang J., Hong Y. Caspases: A Molecular Switch Node in the Crosstalk between Autophagy and Apoptosis. International Journal of Biological Sciences, 2014, vol. 10, DOI:https://doi.org/10.7150/ijbs.9719.
9. Harmaza Y.M., Tamashevski A.V., Kanash J.S., Zubritskaya G.P., Kutko A.G., Slobozhanina E.I. Intracellular Zinc: a Role in H2O2-Induced Oxidative Stress in Human Erythrocytes. Biophysics, 2016, vol. 61. DOI:https://doi.org/10.1134/S0006350916060087.
10. Garmaza Yu.M., Tamashevskiy A.V., Goncharova N.V., Slobozhanina E.I. Vliyanie vnutrikletochnogo urovnya ionov cinka na pereraspredelenie fosfatidilserina v membranah i zhiznesposobnost' eritrocitov cheloveka. Novosti mediko-biologicheskih nauk, 2011, t. 3, № 1, c. 90-95. @@[Harmaza Y.M., Tamashevski A.V., Goncharova N.V., Slobozhanina E.I. Intracellular zinc level effect on the phosphatidylserine redistribution in membranes and viability of human erythrocytes. News of biomedical sciences, 2011, vol. 3, no. 1, p. 90-95. (In Russ)]
11. Harmaza Y., Slobozhanina E. Zinc homeostasis and eryptosis. FEBS Journal, 2013, vol. 280, suppl. 1. DOI:https://doi.org/10.1111/febs.12339.
12. Raftos J.E., Whillier S., Chapman B.E., Kuchel P.W. Kinetics of uptake and deacetylation of N-acetylcysteine by human erythrocytes. The International Journal of Biochemistry & Cell Biology, 2007, vol. 39, no. 9. DOI:https://doi.org/10.1016/j.biocel.2007.04.014.
13. Yildiz D., Bagdadioglu T. L-systeine uptake is stimulated by 1-shloro-2,4-dinitrobenzene in vitro in human erythrocytes. Toxicology Mechanisms and Methods, 2004, vol. 14. DOI:https://doi.org/10.1080/10715760600602902.
14. Tamashevski A.V., Harmaza Y.M., Slobozhanina E.I., Svirnovski A.I. The transport activity of P-glycoprotein upon a change of the redox balance in lymphocytes of patients with chronic B-lymphocytic leukemia. Biophysics, 2016, vol. 61. DOI:https://doi.org/10.1134/S0006350916060257.
15. Ye B., Maret W., Vallee B.L. Zinc metallothionein imported into liver mitochondria modulates respiration. Proc. Natl. Acad. Sci. U.S.A, 2001, vol. 98, no. 5. DOI:https://doi.org/10.1073/pnas.041619198.
16. Khatai L., Goessler W., Lorencova H., Zangger K. Modulation of nitric oxide-mediated metal release from metallothionein by the redox state of glutathione in vitro. Eur. J. Biochem., 2004, vol. 271, no. 12. DOIhttps://doi.org/10.1111/j.1432-1033.2004.04160.x.
17. Dineley K.E., Votyakova T.V., Reynolds I.J. Zinc inhibition of cellular energy production: implications for mitochondria and neurodegeneration. Journal of Neurochemistry, 2003, vol. 85, no. 3. DOI:https://doi.org/10.1046/j.1471-4159.2003.01678.x.
18. Dineley K.E., Richards L.L., Votyakova T.V., Reynolds I.J. Zinc causes loss of membrane potential and ele-vates reactive oxygen species in rat brain mitochondria. Mitochondrion, 2005, vol. 5, no. 1. DOI:https://doi.org/10.1016/j.mito.2004.11.001.
19. Dineley K.E., Scanlon J.M., Kress G.J., Stout A.K., Reynolds I.J. Astrocytes are more resistant than neurons to the cytotoxic effects of increased [Zn2+]i. Neurobiology of Disease, 2000, vol. 7, no. 4. DOI:https://doi.org/10.1006/nbdi.2000.0303.
20. Sensi S.L., Yin H.Z., Carriedo S.G., Rao S.S., Weiss J. H. Preferential Zn2+ influx through Ca2+ permeable AMPA/kainate channels triggers prolonged mitochondrial superoxide production. Proc. Natl. Acad. Sci. U.S.A, 1999, vol. 96, no. 5. DOI:https://doi.org/10.1073/pnas.96.5.2414.
21. Napolitano R., De Matteis S., Lucchesi A., Carloni S., Cangini D., Musuraca G., Liardo E.V., Norata M., Fattori P.P. Pentoxifylline-Induced Apoptosis in Chronic Lymphocytic Leukemia: New Insights into Molecular Mechanism. Mini-Reviews in Medicinal Chemistry, 2018, vol. 18, no. 3. DOI:https://doi.org/10.2174/1389557517666171002162258.
22. Rozovski U., Harris D.M., Li P., Liu Z., Wu J.Y., Grgurevic S., Faderl S., Ferrajoli A., Wierda W.G., Martinez M., Verstovsek S., Keating M.J., Estrov Z. At High Levels, Constitutively Activated STAT3 Induces Apoptosis of Chronic Lymphocytic Leukemia Cells. Journal of Immunology, 2016, vol. 196, no. 10. DOI:https://doi.org/10.4049/jimmunol.1402108.
