Shlapatska Larysa M., Berdova Ganna G., Kovalevska Larysa M., Kulyk Galyna I., Klein George, Sidorenko Svitlana P., Chekhun Vasyl F.

Aim: To understand the biochemical basis of cell sensitivity to cytotoxic effect of doxorubicine (DOX), we investigated signaling cascades mediated by c-Jun N-terminal protein kinases (JNK1/2), p38 mitogen-activated protein kinases (MAPK), extracellular signal-regulated protein kinase (ERK1/2) and protein kinase B/Akt in both DOX-sensitive BL41 and the DOX-resistant DG75 Burkitt’s lymphoma (BL) cell lines. Methods: To test the effect of DOX on different signaling cascades, BL41 and DG75 cells were treated with DOX for varying lengths of time. Cytotoxic effect of DOX was analyzed by Hoechst 33342 staining. Total amount of JNK1/2, ERK1/2, p38 MARK, Akt proteins, and also phosphorylated/activated forms of these enzymes were detected using Western blot analysis with specific antibodies. Immunophenotypic analysis of BL41 and DG75 cells was performed by indirect immunofluorescence staining. Results: Our findings demonstrated that DOX treatment of the BL41 cells led to sustained activation of JNK1/2 and p38 MAPK. This activation/phosphorylation did not result from increased expression of either JNK1/2 or p38 MAPK since protein levels of JNK1/2 and p38 MAPK in DOX-treated and untreated cells were unaltered. Apoptotic signaling cascade induced by DOX in BL41 cell was accompanied by Akt dephosphorylation. The effect of DOX in drug-resistant cell line DG75 convoyed by dephosphorylation of JNK1/2, p38 MAPK and activation of Akt. Fate of BL cells did not depend from ERK activity. Conclusion: The outcome of cellular response to DOX in BL cell lines is determined by interference of at least three signaling pathways: JNK1/2, p38 MAPK and PKB/Akt. The balance between Akt/PKB and MAPK pathways is important in determining whether BL cells survive or undergo apoptosis in response to DOX treatment.

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