Expression of sialidase Neu2 in leukemic K562 cells induces apoptosis by impairing Bcr-Abl/Src kinases signaling.
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.
Tringali
Cristina
C
Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milan, LITA via Fratelli Cervi 93, Segrate, Milan, Italy.
Lupo
Barbara
B
Anastasia
Luigi
L
Papini
Nadia
N
Monti
Eugenio
E
Bresciani
Roberto
R
Tettamanti
Guido
G
Venerando
Bruno
B
D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation; D015536:Down-Regulation; D005455:Fluorescent Antibody Technique; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins; D006801:Humans; D020014:K562 Cells / Q000201:enzymology; D009439:Neuraminidase / Q000378:metabolism*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013107:Sphingolipids; D014443:Tyrosine / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism*
D006023:Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013107:Sphingolipids; D051020:bcl-X Protein; D014443:Tyrosine; D016044:Fusion Proteins, bcr-abl; D016392:Proto-Oncogene Proteins pp60(c-src); C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C403285:NEU2 protein, human; D009439:Neuraminidase