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

Azhar R. Hussain, Shahab Uddin, Maqbool Ahmed, Rong Bu, Saeeda O. Ahmed, Jehad Abubaker, Mehar Sultana, Dahish Ajarim, Fouad Al-Dayel, Prashant P. Bavi, Khawla S. Al-Kuraya

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)180-190
Number of pages11
JournalJournal of Pathology
Volume222
Issue number2
DOIs
StatePublished - Oct 2010

Keywords

  • AKT
  • Apoptosis
  • DLBCL
  • XIAP

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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