Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling

被引:53
作者
Hussain, Azhar R. [1 ]
Uddin, Shahab [1 ]
Ahmed, Maqbool [1 ]
Bu, Rong [1 ]
Ahmed, Saeeda O. [1 ]
Abubaker, Jehad [1 ]
Sultana, Mehar [1 ]
Ajarim, Dahish [2 ]
Al-Dayel, Fouad [3 ]
Bavi, Prashant P. [1 ]
Al-Kuraya, Khawla S. [1 ]
机构
[1] King Faisal Specialist Hosp & Res Ctr, Res Ctr, Riyadh 11211, Saudi Arabia
[2] King Faisal Specialist Hosp & Res Ctr, King Faisal Canc Ctr, Riyadh 11211, Saudi Arabia
[3] King Faisal Specialist Hosp & Res Ctr, Dept Pathol, Riyadh 11211, Saudi Arabia
关键词
XIAP; AKT; apoptosis; DLBCL; B-CELL LYMPHOMA; PRIMARY EFFUSION LYMPHOMA; X-LINKED INHIBITOR; FACTOR-KAPPA-B; CISPLATIN-INDUCED APOPTOSIS; CANCER-CELLS; DEPENDENT INDUCTION; PROTEIN EXPRESSION; STRUCTURAL BASIS; IN-VIVO;
D O I
10.1002/path.2747
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The inhibitor of apoptosis protein (IAP) family member X-linked inhibitor of apoptosis protein (XIAP) is essential for cell survival in lymphoma. However, the role of XIAP overexpression in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Therefore, we analysed the expression of XIAP protein and its clinicopathological correlation in a large cohort of DLBCLs by immunohistochemistry in a tissue micro-array format. XIAP was found to be overexpressed in 55% of DLBCLs and significantly associated with poor clinical outcome (p = 0.0421). To further elucidate the role of XIAP in DLBCL and the inter-relationship with PI3-kinase/AKT signalling, we conducted several in vitro studies using a panel of DLBCL cell lines. We found that pharmacological inhibition of XIAP led to caspase-dependent apoptosis in DLBCL cells. We also detected an inter-relationship between XIAP expression and activated AKT in DLBCL cells that may explain cellular resistance to PI3-kinase/AKT inhibition-mediated apoptosis. Finally, this anti-apoptotic effect was overcome by simultaneous pharmacological inhibition of XIAP and PI3-kinase/AKT signalling leading to a more potent synergistically induced apoptosis. In summary, our data suggest that XIAP expression is a poor prognostic factor in DLBCL and the XIAP-AKT relationship should be explored further as a potential therapeutic target in DLBCL. Copyright (C) 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
引用
收藏
页码:180 / 190
页数:11
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