| RRC ID |
44196
|
| 著者 |
Wu N, Kurosu T, Oshikawa G, Nagao T, Miura O.
|
| タイトル |
PECAM-1 is involved in BCR/ABL signaling and may downregulate imatinib-induced apoptosis of Philadelphia chromosome-positive leukemia cells.
|
| ジャーナル |
Int J Oncol
|
| Abstract |
PECAM-1 (CD31) is an immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing surface glycoprotein expressed on various hematopoietic cells as well as on endothelial cells. PECAM-1 has been shown to play roles in regulation of adhesion, migration and apoptosis. The BCR/ABL fusion tyrosine kinase is expressed in chronic myeloid leukemia and Philadelphia-positive (Ph+) acute lymphoblastic leukemia cells, and its inhibition by the clinically used tyrosine kinase inhibitors imatinib or dasatinib induces apoptosis of these cells. In the present study, we demonstrate that PECAM-1 is tyrosine phospho-rylated in its ITIM motifs in various BCR/ABL-expressing cells including primary leukemia cells. Studies using imatinib and dasatinib as well as transient expression experiments in 293T cells revealed that PECAM-1 was phosphorylated directly by BCR/ABL, which was enhanced by the imatinib-resistant E255K and T315I mutations, or partly by the Src family tyrosine kinases, including Lyn, which were activated dependently or independently on BCR/ABL. We also demonstrate by using a substrate trapping mutant of SHP2 that tyrosine phosphorylated PECAM-1 binds SHP2 and is a major substrate for this tyrosine phosphatase in BCR/ABL-expressing cells. Overexpression of PECAM-1 in BCR/ABL-expressing cells, including K562 human leukemia cells, enhanced cell adhesion and partially inhibited imatinib-induced apoptosis involving mitochondria depolarization and caspase-3 cleavage, at least partly, in an ITIM-independent manner. These data suggest that PECAM-1 may play a role in regulation of apoptosis as well as adhesion of BCR/ABL-expressing cells to modulate their imatinib sensitivity and would be a possible candidate for therapeutic target in Ph+ leukemias.
|
| 巻・号 |
42(2)
|
| ページ |
419-28
|
| 公開日 |
2013-2-1
|
| DOI |
10.3892/ijo.2012.1729
|
| PMID |
23233201
|
| PMC |
PMC3583636
|
| MeSH |
Apoptosis / drug effects
Benzamides / pharmacology*
Cell Adhesion / drug effects
Cell Adhesion / genetics
Drug Resistance, Neoplasm / genetics
Fusion Proteins, bcr-abl / genetics
Fusion Proteins, bcr-abl / metabolism*
Gene Expression Regulation, Neoplastic / drug effects
Humans
Imatinib Mesylate
K562 Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Philadelphia Chromosome
Piperazines / pharmacology*
Platelet Endothelial Cell Adhesion Molecule-1 / genetics
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism*
Pyrimidines / pharmacology*
Signal Transduction / drug effects
|
| IF |
3.899
|
| 引用数 |
7
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
K562 |
