Inhibition of the NEDD8 conjugation pathway induces calciumdependent compensatory activation of the pro-survival MEK/ ERK pathway in acute lymphoblastic leukemia

Shuhua Zheng, Gilles M. Leclerc, Bin Li, Ronan T Swords, Julio Barredo

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat. The observed synergistic apoptotic effect appears to be mediated by inhibition of the MEK/ERK pro-survival cascade leading to de-repression of the pro-apoptotic BIM protein. Mechanistically, Ca2+ influx via the Ca2+-release-activated Ca2+ (CRAC) channel induced protein kinase C β2 (PKC-β2) was responsible for activation of the MEK/ERK pathway in pevonedistat-treated ALL cells. Sequestration of Ca2+ using BAPTA-AM or blockage of store-operated Ca2+ entry (SOCE) using BTP-2 both attenuated the compensatory activation of MEK/ERK signaling in pevonedistat-treated ALL cells. Pevonedistat significantly altered the expression of Orai1 and stromal interaction molecule 1 (STIM1), resulting in significantly decreased STIM1 protein levels relative to Orai1. Further, we identified eIF2α as an important post-transcriptional regulator of STIM1, suggesting that pevonedistat-induced eIF2α de-phosphorylation selectively down-regulates translation of STIM1 mRNA. Consequently, our data suggest that pevonedistat potentially activates SOCE and promotes Ca2+ influx leading to activation of the MEK/ERK pathway by altering the stoichiometric Orai1:STIM1 ratio and inducing ER stress in ALL cells.

Original languageEnglish (US)
Pages (from-to)5529-5544
Number of pages16
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - Jan 1 2018

Fingerprint

MAP Kinase Signaling System
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Mitogen-Activated Protein Kinase Kinases
Recurrence
Apoptosis Regulatory Proteins
Drug Resistance
Protein Kinase C
Down-Regulation
Phosphorylation
Stromal Interaction Molecule 1
Cell Line
Messenger RNA
Enzymes

Keywords

  • Acute lymphoblastic leukemia (ALL)
  • MEK/ERK signaling
  • NEDDylation
  • Pevonedistat
  • Store operated calcium entry

ASJC Scopus subject areas

  • Oncology

Cite this

Inhibition of the NEDD8 conjugation pathway induces calciumdependent compensatory activation of the pro-survival MEK/ ERK pathway in acute lymphoblastic leukemia. / Zheng, Shuhua; Leclerc, Gilles M.; Li, Bin; Swords, Ronan T; Barredo, Julio.

In: Oncotarget, Vol. 9, No. 5, 01.01.2018, p. 5529-5544.

Research output: Contribution to journalArticle

@article{9429ef8d16c74799bf0594b3d909c459,
title = "Inhibition of the NEDD8 conjugation pathway induces calciumdependent compensatory activation of the pro-survival MEK/ ERK pathway in acute lymphoblastic leukemia",
abstract = "De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat. The observed synergistic apoptotic effect appears to be mediated by inhibition of the MEK/ERK pro-survival cascade leading to de-repression of the pro-apoptotic BIM protein. Mechanistically, Ca2+ influx via the Ca2+-release-activated Ca2+ (CRAC) channel induced protein kinase C β2 (PKC-β2) was responsible for activation of the MEK/ERK pathway in pevonedistat-treated ALL cells. Sequestration of Ca2+ using BAPTA-AM or blockage of store-operated Ca2+ entry (SOCE) using BTP-2 both attenuated the compensatory activation of MEK/ERK signaling in pevonedistat-treated ALL cells. Pevonedistat significantly altered the expression of Orai1 and stromal interaction molecule 1 (STIM1), resulting in significantly decreased STIM1 protein levels relative to Orai1. Further, we identified eIF2α as an important post-transcriptional regulator of STIM1, suggesting that pevonedistat-induced eIF2α de-phosphorylation selectively down-regulates translation of STIM1 mRNA. Consequently, our data suggest that pevonedistat potentially activates SOCE and promotes Ca2+ influx leading to activation of the MEK/ERK pathway by altering the stoichiometric Orai1:STIM1 ratio and inducing ER stress in ALL cells.",
keywords = "Acute lymphoblastic leukemia (ALL), MEK/ERK signaling, NEDDylation, Pevonedistat, Store operated calcium entry",
author = "Shuhua Zheng and Leclerc, {Gilles M.} and Bin Li and Swords, {Ronan T} and Julio Barredo",
year = "2018",
month = "1",
day = "1",
doi = "10.18632/oncotarget.23797",
language = "English (US)",
volume = "9",
pages = "5529--5544",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "5",

}

TY - JOUR

T1 - Inhibition of the NEDD8 conjugation pathway induces calciumdependent compensatory activation of the pro-survival MEK/ ERK pathway in acute lymphoblastic leukemia

AU - Zheng, Shuhua

AU - Leclerc, Gilles M.

AU - Li, Bin

AU - Swords, Ronan T

AU - Barredo, Julio

PY - 2018/1/1

Y1 - 2018/1/1

N2 - De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat. The observed synergistic apoptotic effect appears to be mediated by inhibition of the MEK/ERK pro-survival cascade leading to de-repression of the pro-apoptotic BIM protein. Mechanistically, Ca2+ influx via the Ca2+-release-activated Ca2+ (CRAC) channel induced protein kinase C β2 (PKC-β2) was responsible for activation of the MEK/ERK pathway in pevonedistat-treated ALL cells. Sequestration of Ca2+ using BAPTA-AM or blockage of store-operated Ca2+ entry (SOCE) using BTP-2 both attenuated the compensatory activation of MEK/ERK signaling in pevonedistat-treated ALL cells. Pevonedistat significantly altered the expression of Orai1 and stromal interaction molecule 1 (STIM1), resulting in significantly decreased STIM1 protein levels relative to Orai1. Further, we identified eIF2α as an important post-transcriptional regulator of STIM1, suggesting that pevonedistat-induced eIF2α de-phosphorylation selectively down-regulates translation of STIM1 mRNA. Consequently, our data suggest that pevonedistat potentially activates SOCE and promotes Ca2+ influx leading to activation of the MEK/ERK pathway by altering the stoichiometric Orai1:STIM1 ratio and inducing ER stress in ALL cells.

AB - De novo and acquired drug resistance and subsequent relapse remain major challenges in acute lymphoblastic leukemia (ALL). We previously identified that pevonedistat (TAK-924, MLN4924), a first-in-class inhibitor of NEDD8 activating enzyme (NAE), elicits ER stress and has potent in vitro and in vivo efficacy against ALL. However, in pevonedistat-treated ALL cell lines, we found consistent activation of the pro-survival MEK/ERK pathway, which has been associated with relapse and poor outcome in ALL. We uncovered that inhibition of the MEK/ERK pathway in vitro and in vivo sensitized ALL cells to pevonedistat. The observed synergistic apoptotic effect appears to be mediated by inhibition of the MEK/ERK pro-survival cascade leading to de-repression of the pro-apoptotic BIM protein. Mechanistically, Ca2+ influx via the Ca2+-release-activated Ca2+ (CRAC) channel induced protein kinase C β2 (PKC-β2) was responsible for activation of the MEK/ERK pathway in pevonedistat-treated ALL cells. Sequestration of Ca2+ using BAPTA-AM or blockage of store-operated Ca2+ entry (SOCE) using BTP-2 both attenuated the compensatory activation of MEK/ERK signaling in pevonedistat-treated ALL cells. Pevonedistat significantly altered the expression of Orai1 and stromal interaction molecule 1 (STIM1), resulting in significantly decreased STIM1 protein levels relative to Orai1. Further, we identified eIF2α as an important post-transcriptional regulator of STIM1, suggesting that pevonedistat-induced eIF2α de-phosphorylation selectively down-regulates translation of STIM1 mRNA. Consequently, our data suggest that pevonedistat potentially activates SOCE and promotes Ca2+ influx leading to activation of the MEK/ERK pathway by altering the stoichiometric Orai1:STIM1 ratio and inducing ER stress in ALL cells.

KW - Acute lymphoblastic leukemia (ALL)

KW - MEK/ERK signaling

KW - NEDDylation

KW - Pevonedistat

KW - Store operated calcium entry

UR - http://www.scopus.com/inward/record.url?scp=85040682965&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040682965&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.23797

DO - 10.18632/oncotarget.23797

M3 - Article

AN - SCOPUS:85040682965

VL - 9

SP - 5529

EP - 5544

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 5

ER -