In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C

Leukemia
Thomas KindlerThomas Fischer

Abstract

In BCR-ABL-positive cells, the transcription factor STAT-5 is constitutively activated by tyrosine phosphorylation. STAT-5 activation results in upregulation of bcl-X(L) and increased resistance to induction of apoptosis. Here, we investigated the effects of imatinib mesylate and cytosine arabinoside (Ara-C) on STAT-5 tyrosine-phosphorylation, cellular proliferation and induction of apoptosis in cell lines and primary hematopoietic cells. Imatinib mesylate treatment strongly suppressed STAT-5 tyrosine-phosphorylation in K562 and primary CML blasts. In contrast to JAK-2 and PI-3-kinase inhibition, exposure of K562 cells to imatinib mesylate resulted in obvious suppression of proliferation. Reduced cell growth was due to specific induction of caspase activation followed by apoptotic cell death. In addition, we investigated the effects of Ara-C on STAT-5 tyrosine-phosphorylation. Exposure to Ara-C resulted in significant downregulation of STAT-5 tyrosine-phosphorylation and inhibition of DNA binding. Treatment of K562 cells with Ara-C in combination with imatinib mesylate revealed synergistic effects at the level of STAT-5 tyrosine-phosphorylation and DNA binding, Hck tyrosine-phosphorylation, cell growth and induction of apoptosi...Continue Reading

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Citations

Jul 26, 2012·Blood Cancer Journal·S KasperT Fischer
Dec 7, 2007·Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research·Stefan KasperThomas Fischer
Apr 11, 2007·Molecular and Cellular Biology·Yuan-Yeh Kuo, Zee-Fen Chang
Sep 24, 2005·Clinical and Laboratory Haematology·R SwordsP T Murphy
Mar 18, 2009·International Journal of Cancer. Journal International Du Cancer·Jin-Hwang LiuCheng-Hwai Tzeng
Nov 15, 2014·Cell Death and Differentiation·T M SchnöderT Fischer
Apr 1, 2012·JAK-STAT·Michal Bar-NatanDavid A Frank
Oct 25, 2016·ACS Medicinal Chemistry Letters·Xuewu LiangYingjie Zhang
Apr 23, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Encarnacion Montecino-RodriguezKenneth Dorshkind
Dec 24, 2019·Technology in Cancer Research & Treatment·Mohammed Hussein KamareddineSaid Farhat
Mar 13, 2010·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Fabrizio Condorelli, Armando A Genazzani
Jul 31, 2004·Science·Raffaella SordellaJeffrey Settleman

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