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

Adam S. Kittai; Olga V. Danilova; Vi Lam; Tingting Liu; Nur Bruss; Scott Best; Guang Fan; Alexey V. Danilov

doi:10.18632/ONCOTARGET.28063

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

Adam S. Kittai, Olga V. Danilova, Vi Lam, Tingting Liu, Nur Bruss, Scott Best, Guang Fan, Alexey V. Danilov

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27^Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

Original language	English (US)
Pages (from-to)	2068-2074
Number of pages	7
Journal	Oncotarget
Volume	12
Issue number	20
DOIs	https://doi.org/10.18632/ONCOTARGET.28063
State	Published - Sep 28 2021

Keywords

Anaphase catastrophe
Chromosomal instability
Pevonedistat
T-cell lymphoma

ASJC Scopus subject areas

Oncology

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10.18632/ONCOTARGET.28063

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

abstract = "Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.",

keywords = "Anaphase catastrophe, Chromosomal instability, Pevonedistat, T-cell lymphoma",

author = "Kittai, {Adam S.} and Danilova, {Olga V.} and Vi Lam and Tingting Liu and Nur Bruss and Scott Best and Guang Fan and Danilov, {Alexey V.}",

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year = "2021",

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doi = "10.18632/ONCOTARGET.28063",

language = "English (US)",

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T1 - NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells

AU - Kittai, Adam S.

AU - Danilova, Olga V.

AU - Lam, Vi

AU - Liu, Tingting

AU - Bruss, Nur

AU - Best, Scott

AU - Fan, Guang

AU - Danilov, Alexey V.

PY - 2021/9/28

Y1 - 2021/9/28

N2 - Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

AB - Peripheral T-cell lymphoma (PTCL) is characterized by poor outcomes. We and others have shown that targeting the NEDD8-activating enzyme (NAE) with an investigational inhibitor pevonedistat deregulates cell cycle and mitosis in lymphoma and leukemia. Here, we report that PTCL is characterized by increased rate of chromosomal instability. NAE inhibition promotes cell cycle arrest and induces multipolar anaphases in T-cell lymphoma cell lines, resulting in apoptosis, also observed in primary malignant PTCL cells treated with pevonedistat. We identified p27Kip1 as a mediator of anaphase catastrophe in these cells. Targeting neddylation with pevonedistat may be a promising approach to treatment of PTCL.

KW - Anaphase catastrophe

KW - Chromosomal instability

KW - Pevonedistat

KW - T-cell lymphoma

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

Abstract

Keywords

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