STAT5 inhibition induces TRAIL/DR4 dependent apoptosis in peripheral T-cell lymphoma
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Haley M. Simpson1,2,3, Aki Furusawa1,2,3, Kavitha Sadashivaiah1,2,3, Curt I. Civin2,3,4 and Arnob Banerjee1,2,3
1Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
2Program in Oncology, Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
3Center for Stem Cell Biology & Regenerative Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
4Department of Physiology and Pediatrics, University of Maryland School of Medicine, Baltimore, MD, USA
Haley M. Simpson, email: firstname.lastname@example.org
Keywords: STAT5; JAK/STAT; pimozide; peripheral T cell lymphoma; apoptosis
Received: July 07, 2017 Accepted: February 28, 2018 Published: March 30, 2018
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.
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