title: Aberrant localization of apoptosis protease activating factor-1 in lipid raft sub-domains of diffuse large B cell lymphomas.
abstract: Resistance to chemotherapy remains a challenge in the clinical management of diffuse B cell lymphomas despite aggressive chemotherapy such as CHOP and monoclonal CD20. Here we provide evidence that the apoptosome adaptor protein, Apaf-1, is mislocalized in primary cells derived from patients with diffuse large B cell lymphomas (DLBCL). Whereas, the total expression of Apaf-1 did not change, its sub-cellular localization was significantly different in DLBCL, compared to T cell lymphomas as well as cells derived from reactive lymphadenopathy biopsies. As expected, Apaf-1 was detected in the cytosolic fractions of non-B cell lymphomas and non-cancerous tissues; however, in B cell derived lymphomas the protein was detected in membrane raft sub-domains rather than the cytosol. Disruption of lipid raft structures resulted in the redistribution of Apaf-1 to the cytosol and restored apoptosis sensitivity of DLBCL. Furthermore, we identified novel small molecule compounds that target DLBCL by promoting Apaf-1 release form lipid rafts via mechanisms that involve an increase in intracellular reactive oxygen species production. Taken together, our results implicate Apaf-1 mislocalization as a potential diagnostic and prognostic marker for DLBCL, and provide a novel therapeutic strategy for circumventing the drug refractory nature of this sub-class of B cell lymphoma.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Experimental Therapeutics Program, Cancer Science Institute, National University Healthcare System, Singapore.
authors.forename: Jayshree L
authors.initials: JL
authors.lastname: Hirpara
authors.affiliation: Department of Otolaryngology, National University Healthcare System, Singapore.
authors.forename: Thomas
authors.initials: T
authors.lastname: Loh
authors.affiliation: Department of Pathology, National University Healthcare System, Singapore.
authors.forename: Siok Bian
authors.initials: SB
authors.lastname: Ng
authors.affiliation: Cancer Science Institute, National University Healthcare System, Singapore.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.|National University Cancer Institute, National University Healthcare System,.|School of Biomedical Sciences, Curtin University, Perth, Australia.
authors.forename: Shazib
authors.initials: S
authors.lastname: Pervaiz
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D019169:Jurkat Cells; D015227:Lipid Peroxidation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C506592:APAF1 protein, human; D000970:Antineoplastic Agents; D053477:Apoptotic Protease-Activating Factor 1; D017382:Reactive Oxygen Species; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Apaf-1; Autophagy; DLBCL; ROS; apoptosome; lipid rafts