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    STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma

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    Author
    Simpson, H.M.
    Furusawa, A.
    Sadashivaiah, K.
    Date
    2018
    Journal
    Oncotarget
    Publisher
    Impact Journals LLC
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.18632/oncotarget.24698
    Abstract
    Peripheral 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.
    Keyword
    Apoptosis
    JAK/STAT
    Peripheral T cell lymphoma
    Pimozide
    STAT5
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85044758813&doi=10.18632%2foncotarget.24698&partnerID=40&md5=01a726134f3c7cfc1a22c12ad8d0308e; http://hdl.handle.net/10713/9089
    ae974a485f413a2113503eed53cd6c53
    10.18632/oncotarget.24698
    Scopus Count
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    UMB Open Access Articles 2018

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