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dc.contributor.authorSimpson, H.M.
dc.contributor.authorFurusawa, A.
dc.contributor.authorSadashivaiah, K.
dc.date.accessioned2019-05-17T12:53:05Z
dc.date.available2019-05-17T12:53:05Z
dc.date.issued2018
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85044758813&doi=10.18632%2foncotarget.24698&partnerID=40&md5=01a726134f3c7cfc1a22c12ad8d0308e
dc.identifier.urihttp://hdl.handle.net/10713/9089
dc.description.abstractPeripheral T-cell lymphoma (PTCL) is a rare, aggressive, heterogeneous, Non- Hodgkin's lymphoma with poor prognosis and inadequate response to current therapies. Recent sequencing studies indicate a prevalence of activating mutations in the JAK/STAT signaling pathway. Oncogenic mutations in STAT5B, observed in approximately one third of cases of multiple different PTCL subtypes, correlate with inferior patient outcomes. Therefore, interest in the development of therapeutic strategies for targeting STAT5 in PTCL is warranted. In this study, we show that the drug pimozide inhibits STAT5 in PTCL, leading to apoptotic cell death by means of the TRAIL/DR4 dependent extrinsic apoptotic pathway. Pimozide induced PTCL cell death is caspase 8 dependent, increases the expression of the TRAIL receptor, DR4, on the surface of pre-apoptotic PTCL cells, and enhances TRAIL induced apoptosis in a TRAIL dependent manner. In parallel, we show that mRNA and protein levels of intrinsic pathway BCL-2 family members and mitochondrial membrane potential remain unaffected by STAT5 knockdown and/or inhibition. In primary PTCL patient samples, pimozide inhibits STAT5 activation and induces apoptosis. Our data support a role for STAT5 inhibition in PTCL and implicate potential utility for inhibition of STAT5 and activation of the extrinsic apoptotic pathway as combination therapy in PTCL. Copyright Simpson et al.en_US
dc.description.urihttps://dx.doi.org/10.18632/oncotarget.24698en_US
dc.language.isoen_USen_US
dc.publisherImpact Journals LLCen_US
dc.relation.ispartofOncotarget
dc.subjectApoptosisen_US
dc.subjectJAK/STATen_US
dc.subjectPeripheral T cell lymphomaen_US
dc.subjectPimozideen_US
dc.subjectSTAT5en_US
dc.titleSTAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphomaen_US
dc.typeArticleen_US
dc.identifier.doi10.18632/oncotarget.24698


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