Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway

Mercedes Lioni, Kazuhiro Noma, Andrew Snyder, Andres Klein-Szanto, J. Alan Diehl, Anil K. Rustgi, Meenhard Herlyn, Keiran S M Smalley

Research output: Contribution to journalArticle

41 Citations (Scopus)

Abstract

Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate 2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.

Original languageEnglish
Pages (from-to)2866-2875
Number of pages10
JournalMolecular Cancer Therapeutics
Volume7
Issue number9
DOIs
Publication statusPublished - 2008
Externally publishedYes

Fingerprint

p38 Mitogen-Activated Protein Kinases
Apoptosis
Noxae
Phosphotransferases
M Phase Cell Cycle Checkpoints
Therapeutics
Caspases
Mitogen-Activated Protein Kinases
Small Interfering RNA
Bortezomib
Esophageal Squamous Cell Carcinoma
Up-Regulation
Radiotherapy
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway. / Lioni, Mercedes; Noma, Kazuhiro; Snyder, Andrew; Klein-Szanto, Andres; Diehl, J. Alan; Rustgi, Anil K.; Herlyn, Meenhard; Smalley, Keiran S M.

In: Molecular Cancer Therapeutics, Vol. 7, No. 9, 2008, p. 2866-2875.

Research output: Contribution to journalArticle

Lioni, Mercedes ; Noma, Kazuhiro ; Snyder, Andrew ; Klein-Szanto, Andres ; Diehl, J. Alan ; Rustgi, Anil K. ; Herlyn, Meenhard ; Smalley, Keiran S M. / Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 9. pp. 2866-2875.
@article{1b8f195295734a5fa2eb04a0e8d0ccff,
title = "Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway",
abstract = "Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate 2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.",
author = "Mercedes Lioni and Kazuhiro Noma and Andrew Snyder and Andres Klein-Szanto and Diehl, {J. Alan} and Rustgi, {Anil K.} and Meenhard Herlyn and Smalley, {Keiran S M}",
year = "2008",
doi = "10.1158/1535-7163.MCT-08-0391",
language = "English",
volume = "7",
pages = "2866--2875",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Bortezomib induces apoptosis in esophageal squamous cell carcinoma cells through activation of the p38 mitogen-activated protein kinase pathway

AU - Lioni, Mercedes

AU - Noma, Kazuhiro

AU - Snyder, Andrew

AU - Klein-Szanto, Andres

AU - Diehl, J. Alan

AU - Rustgi, Anil K.

AU - Herlyn, Meenhard

AU - Smalley, Keiran S M

PY - 2008

Y1 - 2008

N2 - Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate 2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.

AB - Esophageal squamous cell carcinoma (ESCC) is an exceptionally drug-resistant tumor with a 5-year survival rate 2-M-phase cell cycle arrest and p53-independent apoptosis associated with caspase cleavage and Noxa induction. Bortezomib also showed excellent activity in organotypic culture and in vivo models of ESCC. Biochemically, bortezomib treatment activated the p38 and c-Jun NH2-termnial kinase stress-activated mitogen-activated protein kinase (MAPK) pathways and induced phospho-H2AX activity. Although H2AX is known to cooperate with c-Jun NH2-termnial kinase to induce apoptosis following UV irradiation, knockdown of H2AX did not abrogate bortezomib-induced apoptosis. Instead, blockade of p38 MAPK signaling, using either small interfering RNA or a pharmacologic inhibitor, reversed bortezomib-induced apoptosis and the up-regulation of Noxa. Radiation therapy is known to activate the p38 MAPK pathway and is a mainstay of ESCC treatment strategies. In a final series of studies, we showed that the coadministration of bortezomib with irradiation led to enhanced p38 MAPK activity and a significant reduction in colony formation. We therefore suggest that p38 MAPK pathway activation is an excellent potential therapeutic strategy in ESCC. It is further suggested that bortezomib could be added to existing ESCC therapeutic regimens.

UR - http://www.scopus.com/inward/record.url?scp=54049085820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=54049085820&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-08-0391

DO - 10.1158/1535-7163.MCT-08-0391

M3 - Article

C2 - 18790767

AN - SCOPUS:54049085820

VL - 7

SP - 2866

EP - 2875

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 9

ER -