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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-02-0539. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-02-0539v1 100/10/3741    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ringshausen, I. Articles by Decker, T. Search for Related Content PubMed PubMed Citation Articles by Ringshausen, I. Articles by Decker, T. Related Collections Signal Transduction Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 November 2002, Vol. 100, No. 10, pp. 3741-3748 NEOPLASIA Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase C Ingo Ringshausen, Folker Schneller, Christian Bogner, Susanne Hipp, Justus Duyster, Christian Peschel, and Thomas Decker From the Third Department of Medicine, Technical University of Munich, Germany. In the present study we analyzed the role of phophatidylinositol-3 kinase (PI-3K) in B chronic lymphocytic leukemia (B-CLL) cells. PI-3K is activated by many stimuli and is linked to several different signaling pathways. We demonstrated that inhibition of PI-3K by a specific inhibitor, LY294002, induced apoptosis in B-CLL cells in vitro. This effect was specific for the inhibition of PI-3K because inhibition of other signaling pathways such as extracellular signaling-regulated kinase (ERK), p38, or p70S6 kinase did not affect spontaneous apoptosis. Furthermore, PI-3K was constitutively activated in freshly isolated B-CLL cells. Corresponding to enhanced apoptosis, LY294002 down-regulated expression of the antiapoptotic proteins X-linked inhibitor of apoptosis protein (XIAP) and Mcl-1. Next, we investigated which factors downstream of PI-3K were activated in B-CLL cells. We demonstrated that protein kinase B/Akt is expressed in all tested CLL samples but no activation of Akt was detected. In contrast, we observed a constitutive activation of protein kinase C (PKC) in freshly isolated B-CLL cells. PKC is linked to PI-3K and is phosphorylated at Thr505 in response to PI-3K activation. We further demonstrated that tyrosine phosphorylation and activity of PKC were dependent on PI-3K activity in B-CLL cells. Inhibition of PKC by the specific inhibitor Rottlerin strikingly enhanced apoptosis. In contrast, peripheral blood B cells of healthy donors were resistant to inhibition of PI-3K or PKC. We conclude that activated PI-3K might be important in the pathogenesis of B-CLL, and survival signals might be mediated via PKC. Therefore, inhibition of PI-3K or PKC may be an innovative approach to treat B-CLL. © 2002 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Plate Signals that maintain leukemic cell viability Blood, July 1, 2008; 112(1): 1 - 2. [Full Text] [PDF] M. Muzio, B. Apollonio, C. Scielzo, M. Frenquelli, I. Vandoni, V. Boussiotis, F. Caligaris-Cappio, and P. Ghia Constitutive activation of distinct BCR-signaling pathways in a subset of CLL patients: a molecular signature of anergy Blood, July 1, 2008; 112(1): 188 - 195. [Abstract] [Full Text] [PDF] T. 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