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The association of up‐regulation of X‐linked inhibitor of apoptosis protein with cell adhesion‐mediated drug resistance in U937 cells
Author(s) -
Wang Xiaofang,
Wang Chun,
Qin Youwen,
Yan Shike,
Gao Yanrong
Publication year - 2008
Publication title -
hematological oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 44
eISSN - 1099-1069
pISSN - 0278-0232
DOI - 10.1002/hon.828
Subject(s) - xiap , daunorubicin , u937 cell , cancer research , pi3k/akt/mtor pathway , inhibitor of apoptosis , cell adhesion , protein kinase b , apoptosis , microbiology and biotechnology , chemistry , biology , signal transduction , cell , immunology , programmed cell death , leukemia , biochemistry , caspase
An increasing body of evidence indicates that environmental factors may contribute to the drug resistance of acute myeloid leukaemia (AML). CAM‐DR (cell adhesion‐mediated drug resistance) is a reversible, de novo drug resistance induced by adhesion of tumour cell lines to fibronectin (FN). Adhesion was demonstrated to directly regulate the apoptotic machinery. And it was observed in previous studies that high levels of X‐linked inhibitor of apoptosis protein (XIAP) were related to resistance to chemotherapeutics in many cancer cell lines. However, whether XIAP is relevant to CAM‐DR of AML cells is unknown. In this report, we demonstrated that the mRNA and protein levels of XIAP were increased by 96.15% and 120.92%, respectively in U937 cells cocultured with FN as compared with controls. Antisense oligonucleotides targeting XIAP down‐regulated the expression of XIAP and sensitized U937 cells to daunorubicin. In addition, we investigated the signalling pathway involved in the upregulation of XIAP. The levels of phosphorylated Akt (Ser473) were elevated in U937/FN cells and the phosphatidylinositol 3‐kinase (PI3K) inhibitor LY294002 suppressed XIAP expression and restored the chemosensitivity to daunorubicin. Our findings suggested that adhesion‐dependent activation of the PI3K/Akt/XIAP pathway may be one of the factors involved in the CAM‐DR of U937 cells. Targeting this pathway may be a useful approach to improve the therapeutic responsiveness of leukaemia cells. Copyright © 2007 John Wiley & Sons, Ltd.