Elevated pressure enhanced trail-induced apoptosis in hepatocellular carcinoma cells via erk1/2-inactivation

Eunyoung Hong, Eun Il Lee, Joonhee Kim, Daeho Kwon, Yongchul Lim

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

Original languageEnglish
Pages (from-to)535-548
Number of pages14
JournalCellular and Molecular Biology Letters
Volume20
Issue number4
DOIs
Publication statusPublished - 2015 Dec 1

Fingerprint

Hepatocellular Carcinoma
Cells
Apoptosis
Ligands
Pressure
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Protein Kinases
Phosphorylation
Chemical activation
Tumors
Caspases
Tumor Cell Line
Carcinoma
Lung
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
Neoplasms

Keywords

  • Apoptosis
  • BAD
  • CREB
  • Elevated pressure
  • ERK1/2
  • Hepatocellular carcinoma
  • Mechanical stress
  • TRAIL

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Elevated pressure enhanced trail-induced apoptosis in hepatocellular carcinoma cells via erk1/2-inactivation. / Hong, Eunyoung; Lee, Eun Il; Kim, Joonhee; Kwon, Daeho; Lim, Yongchul.

In: Cellular and Molecular Biology Letters, Vol. 20, No. 4, 01.12.2015, p. 535-548.

Research output: Contribution to journalArticle

@article{cc3e7f57899447a58679351c8335f379,
title = "Elevated pressure enhanced trail-induced apoptosis in hepatocellular carcinoma cells via erk1/2-inactivation",
abstract = "The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.",
keywords = "Apoptosis, BAD, CREB, Elevated pressure, ERK1/2, Hepatocellular carcinoma, Mechanical stress, TRAIL",
author = "Eunyoung Hong and Lee, {Eun Il} and Joonhee Kim and Daeho Kwon and Yongchul Lim",
year = "2015",
month = "12",
day = "1",
doi = "10.1515/cmble-2015-0030",
language = "English",
volume = "20",
pages = "535--548",
journal = "Cellular and Molecular Biology Letters",
issn = "1425-8153",
publisher = "Springer Verlag",
number = "4",

}

TY - JOUR

T1 - Elevated pressure enhanced trail-induced apoptosis in hepatocellular carcinoma cells via erk1/2-inactivation

AU - Hong, Eunyoung

AU - Lee, Eun Il

AU - Kim, Joonhee

AU - Kwon, Daeho

AU - Lim, Yongchul

PY - 2015/12/1

Y1 - 2015/12/1

N2 - The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

AB - The high frequency of intrinsic resistance to TNF-related apoptosisinducing ligand (TRAIL) in tumor cell lines has necessitated the development of strategies to sensitize tumors to TRAIL-induced apoptosis. We previously showed that elevated pressure applied as a mechanical stressor enhanced TRAIL-mediated apoptosis in human lung carcinoma cells in vitro and in vivo. This study focused on the effect of elevated pressure on the sensitization of TRAIL-resistant cells and the underlying mechanism. We observed elevated pressure-induced sensitization to TRAIL-mediated apoptosis in Hep3B cells, accompanied by the activation of several caspases and the mitochondrial signaling pathway. Interestingly, the enhanced apoptosis induced by elevated pressure was correlated with suppression of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) phosphorylation and CREB without any change to other MAPKs. Phosphorylation of Bcl-2-associated death promoter (BAD) also decreased, leading to inhibition of the mitochondrial pathway. To confirm whether the activation of pERK1/2 plays a key role in the TRAIL-sensitizing effect of elevated pressure, Hep3B cells were pre-treated with the ERK1/2-specific inhibitor PD98059 instead of elevated pressure. Co-treatment with PD98059 and TRAIL augmented TRAIL-induced apoptosis and decreased BAD phosphorylation. The inhibition of ERK1/2 activation by elevated pressure and PD98059 also reduced BH3 interacting-domain death agonist (BID), thereby amplifying apoptotic stress at the mitochondrial level. Our results suggest that elevated pressure enhances TRAIL-induced apoptosis of Hep3B cells via specific suppression of ERK1/2 activation among MAPKs.

KW - Apoptosis

KW - BAD

KW - CREB

KW - Elevated pressure

KW - ERK1/2

KW - Hepatocellular carcinoma

KW - Mechanical stress

KW - TRAIL

UR - http://www.scopus.com/inward/record.url?scp=84946564737&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84946564737&partnerID=8YFLogxK

U2 - 10.1515/cmble-2015-0030

DO - 10.1515/cmble-2015-0030

M3 - Article

C2 - 26124051

AN - SCOPUS:84946564737

VL - 20

SP - 535

EP - 548

JO - Cellular and Molecular Biology Letters

JF - Cellular and Molecular Biology Letters

SN - 1425-8153

IS - 4

ER -