title: Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling.
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.
authors.affiliation: Human Cancer Genomic Research, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Rong
authors.initials: R
authors.lastname: Bu
authors.forename: Saeeda O
authors.initials: SO
authors.lastname: Ahmed
authors.forename: Jehad
authors.initials: J
authors.lastname: Abubaker
authors.forename: Mehar
authors.initials: M
authors.lastname: Sultana
authors.forename: Dahish
authors.initials: D
authors.lastname: Ajarim
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Prashant P
authors.initials: PP
authors.lastname: Bavi
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009367:Neoplasm Staging; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; C010945:embelin