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

Haley M Simpson1,2,3, Aki Furusawa1,2,3, Kavitha Sadashivaiah1,2,3

  • 1Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.

Oncotarget
|April 24, 2018
PubMed

Insights

The drug pimozide targets STAT5B mutations common in Peripheral T-cell lymphoma (PTCL), inducing cancer cell death via the TRAIL/DR4 pathway. This offers a potential new therapy for aggressive PTCL with poor prognosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Peripheral T-cell lymphoma (PTCL) is an aggressive non-Hodgkin's lymphoma with poor outcomes.
  • Activating mutations in the JAK/STAT pathway, particularly STAT5B, are prevalent in PTCL and linked to worse prognosis.
  • Targeting STAT5 represents a potential therapeutic strategy for PTCL.

Purpose of the Study:

  • To investigate the efficacy of pimozide, a STAT5 inhibitor, in PTCL.
  • To elucidate the mechanism of pimozide-induced cell death in PTCL.

Main Methods:

  • Utilized PTCL cell lines and primary patient samples.
  • Assessed the effect of pimozide on STAT5 activation, apoptosis, and the TRAIL/DR4 extrinsic pathway.
  • Investigated the role of caspase 8 and TRAIL/DR4 in pimozide-mediated cell death.
  • Examined the impact on intrinsic apoptotic pathway markers.

Main Results:

  • Pimozide effectively inhibits STAT5 activation in PTCL cells and patient samples.
  • Pimozide induces apoptotic cell death through the caspase 8-dependent TRAIL/DR4 extrinsic pathway.
  • Pimozide increases DR4 expression and enhances TRAIL-induced apoptosis.
  • The intrinsic apoptotic pathway and mitochondrial membrane potential were unaffected.

Conclusions:

  • STAT5 inhibition is a viable strategy for PTCL treatment.
  • Pimozide demonstrates therapeutic potential by activating the extrinsic apoptotic pathway.
  • Combination therapy targeting STAT5 and the extrinsic apoptotic pathway may benefit PTCL patients.
Keywords:
JAK/STATSTAT5apoptosisperipheral T cell lymphomapimozide

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