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NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells

Adam S Kittai1,2, Olga V Danilova3,2, Vi Lam3

  • 1The Ohio State University, Columbus, OH 43210, USA.

Oncotarget
|October 6, 2021
PubMed

Insights

Targeting the NEDD8-activating enzyme (NAE) with pevonedistat shows promise for treating Peripheral T-cell lymphoma (PTCL). This approach induces cell cycle arrest and apoptosis in PTCL cells, offering a potential new therapeutic strategy.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Peripheral T-cell lymphoma (PTCL) is an aggressive cancer with poor patient outcomes.
  • Previous research indicates that inhibiting the NEDD8-activating enzyme (NAE) disrupts cell cycle and mitosis in various blood cancers.

Purpose of the Study:

  • To investigate the role of chromosomal instability in PTCL.
  • To evaluate the efficacy of pevonedistat, a NAE inhibitor, in PTCL models.
  • To identify mechanisms underlying pevonedistat's effects in PTCL.

Main Methods:

  • Analysis of chromosomal instability in PTCL.
  • Treatment of T-cell lymphoma cell lines and primary PTCL cells with pevonedistat.
  • Assessment of cell cycle progression, anaphase events, and apoptosis.
  • Identification of key molecular mediators, including p27Kip1.

Main Results:

  • PTCL exhibits an elevated rate of chromosomal instability.
  • NAE inhibition by pevonedistat induced cell cycle arrest and multipolar anaphases in PTCL cell lines.
  • Pevonedistat treatment led to apoptosis in both cell lines and primary malignant PTCL cells.
  • p27Kip1 was identified as a crucial mediator of anaphase catastrophe.

Conclusions:

  • NAE inhibition effectively targets PTCL by inducing cell cycle arrest and apoptosis.
  • Pevonedistat demonstrates potential as a novel therapeutic agent for PTCL.
  • The findings highlight the significance of neddylation pathways in PTCL pathogenesis and treatment.
Keywords:
T-cell lymphomaanaphase catastrophechromosomal instabilitypevonedistat

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