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J. Biol. Chem., Vol. 282, Issue 19, 14364-14372, May 11, 2007

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Expression of Sialidase Neu2 in Leukemic K562 Cells Induces Apoptosis by Impairing Bcr-Abl/Src Kinases Signaling^*

Cristina Tringali, Barbara Lupo, Luigi Anastasia, Nadia Papini, Eugenio Monti, Roberto Bresciani, Guido Tettamanti, and Bruno Venerando¹

From the Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, L.I.T.A. via Fratelli Cervi 93, Segrate, 20090 Milan, Italy and the Department of Biomedical Science and Biotechnology, University of Brescia, viale Europa 11, 25123 Brescia, Italy

Chronic myeloid leukemia is a hematopoietic stem cell cancer, originated by the perpetually "switched on" activity of the tyrosine kinase Bcr-Abl, leading to uncontrolled proliferation and insensitivity to apoptotic stimuli. The genetic phenotype of myeloid leukemic K562 cells includes the suppression of cytosolic sialidase Neu2. Neu2 transfection in K562 cells induced a marked decrease (-30% and -80%) of the mRNA of the anti-apoptotic factors Bcl-XL and Bcl-2, respectively, and an almost total disappearance of Bcl-2 protein. In addition, gene expression and activity of Bcr-Abl underwent a 35% diminution, together with a marked decrease of Bcr-Abl-dependent Src and Lyn kinase activity. Thus, the antiapoptotic axis Bcr-Abl, Src, and Lyn, which stimulates the formation of Bcl-XL and Bcl-2, was remarkably weakened. The ultimate consequences of these modifications were an increased susceptibility to apoptosis of K562 cells and a marked reduction of their proliferation rate. The molecular link between Neu2 activity and Bcr-Abl signaling pathway may rely on the desialylation of some cytosolic glycoproteins. In fact, three cytosolic glycoproteins, in the range 45–66 kDa, showed a 50–70% decrease of their sialic acid content upon Neu2 expression, supporting their possible role as modulators of the Bcr-Abl complex.

Received for publication, January 16, 2007 , and in revised form, March 16, 2007.

^* This work was supported by PRIN (to G. T. and E. M.) and the Italian Ministries of Health and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, Via Fratelli Cervi 93, Segrate, 20090 Milan, Italy. Tel.: 39-02-503-30361; Fax: 39-02-503-30365; E-mail: bruno.venerando{at}unimi.it.

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