Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway

Konstantinos G. Drosopoulos, Michael L. Roberts, Lukas Cermak, Takehiko Sasazuki, Senji Shirasawa, Ladislav Andera, Alexander Pintzas

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

RAS oncogenes play a major role in cancer development by activating an array of signaling pathways, most notably mitogen-activated protein kinases, resulting in aberrant proliferation and inhibition of apoptotic signaling cascades, rendering transformed cells resistant to extrinsic death stimuli. However, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill specific tumor cells through the engagement of its receptors, death receptor 4 (DR4) and death receptor 5 (DR5), and the activation of apoptotic pathways, providing promising targets for anticancer therapies. In this study, we show that TRAIL induces cell death in human colon adenocarcinoma cells in a MEK-dependent manner. We also report a prolonged MEK-dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system. Our study reveals that transformation of the colon cell line Caco-2 by Ki- and mainly by Ha-ras oncogenes sensitizes these cells to TRAIL-induced apoptosis by causing specific MEK-dependent up-regulation of DR4 and DR5. These observations taken together reveal that RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 and overall imply that TRAIL-based therapeutic strategies using TRAIL agonists could be used in cases of human colon cancers bearing RAS mutations.

Original languageEnglish
Pages (from-to)22856-22867
Number of pages12
JournalJournal of Biological Chemistry
Volume280
Issue number24
DOIs
Publication statusPublished - Jun 17 2005
Externally publishedYes

Fingerprint

TNF-Related Apoptosis-Inducing Ligand Receptors
Mitogen-Activated Protein Kinase Kinases
Colon
Apoptosis
Bearings (structural)
Chemical activation
Cells
ras Genes
MAP Kinase Signaling System
Cell death
Mitogen-Activated Protein Kinases
Oncogenes
Colonic Neoplasms
Tumors
Neoplasms
Adenocarcinoma
Cell Death
Up-Regulation
Tumor Necrosis Factor-alpha
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway. / Drosopoulos, Konstantinos G.; Roberts, Michael L.; Cermak, Lukas; Sasazuki, Takehiko; Shirasawa, Senji; Andera, Ladislav; Pintzas, Alexander.

In: Journal of Biological Chemistry, Vol. 280, No. 24, 17.06.2005, p. 22856-22867.

Research output: Contribution to journalArticle

Drosopoulos, Konstantinos G. ; Roberts, Michael L. ; Cermak, Lukas ; Sasazuki, Takehiko ; Shirasawa, Senji ; Andera, Ladislav ; Pintzas, Alexander. / Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 24. pp. 22856-22867.
@article{5b7c36726d7e4b79b690b6c4ba4583ee,
title = "Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway",
abstract = "RAS oncogenes play a major role in cancer development by activating an array of signaling pathways, most notably mitogen-activated protein kinases, resulting in aberrant proliferation and inhibition of apoptotic signaling cascades, rendering transformed cells resistant to extrinsic death stimuli. However, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill specific tumor cells through the engagement of its receptors, death receptor 4 (DR4) and death receptor 5 (DR5), and the activation of apoptotic pathways, providing promising targets for anticancer therapies. In this study, we show that TRAIL induces cell death in human colon adenocarcinoma cells in a MEK-dependent manner. We also report a prolonged MEK-dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system. Our study reveals that transformation of the colon cell line Caco-2 by Ki- and mainly by Ha-ras oncogenes sensitizes these cells to TRAIL-induced apoptosis by causing specific MEK-dependent up-regulation of DR4 and DR5. These observations taken together reveal that RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 and overall imply that TRAIL-based therapeutic strategies using TRAIL agonists could be used in cases of human colon cancers bearing RAS mutations.",
author = "Drosopoulos, {Konstantinos G.} and Roberts, {Michael L.} and Lukas Cermak and Takehiko Sasazuki and Senji Shirasawa and Ladislav Andera and Alexander Pintzas",
year = "2005",
month = "6",
day = "17",
doi = "10.1074/jbc.M412483200",
language = "English",
volume = "280",
pages = "22856--22867",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "24",

}

TY - JOUR

T1 - Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEK-dependent pathway

AU - Drosopoulos, Konstantinos G.

AU - Roberts, Michael L.

AU - Cermak, Lukas

AU - Sasazuki, Takehiko

AU - Shirasawa, Senji

AU - Andera, Ladislav

AU - Pintzas, Alexander

PY - 2005/6/17

Y1 - 2005/6/17

N2 - RAS oncogenes play a major role in cancer development by activating an array of signaling pathways, most notably mitogen-activated protein kinases, resulting in aberrant proliferation and inhibition of apoptotic signaling cascades, rendering transformed cells resistant to extrinsic death stimuli. However, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill specific tumor cells through the engagement of its receptors, death receptor 4 (DR4) and death receptor 5 (DR5), and the activation of apoptotic pathways, providing promising targets for anticancer therapies. In this study, we show that TRAIL induces cell death in human colon adenocarcinoma cells in a MEK-dependent manner. We also report a prolonged MEK-dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system. Our study reveals that transformation of the colon cell line Caco-2 by Ki- and mainly by Ha-ras oncogenes sensitizes these cells to TRAIL-induced apoptosis by causing specific MEK-dependent up-regulation of DR4 and DR5. These observations taken together reveal that RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 and overall imply that TRAIL-based therapeutic strategies using TRAIL agonists could be used in cases of human colon cancers bearing RAS mutations.

AB - RAS oncogenes play a major role in cancer development by activating an array of signaling pathways, most notably mitogen-activated protein kinases, resulting in aberrant proliferation and inhibition of apoptotic signaling cascades, rendering transformed cells resistant to extrinsic death stimuli. However, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to kill specific tumor cells through the engagement of its receptors, death receptor 4 (DR4) and death receptor 5 (DR5), and the activation of apoptotic pathways, providing promising targets for anticancer therapies. In this study, we show that TRAIL induces cell death in human colon adenocarcinoma cells in a MEK-dependent manner. We also report a prolonged MEK-dependent activation of ERK1/2 and increased c-FOS expression induced by TRAIL in this system. Our study reveals that transformation of the colon cell line Caco-2 by Ki- and mainly by Ha-ras oncogenes sensitizes these cells to TRAIL-induced apoptosis by causing specific MEK-dependent up-regulation of DR4 and DR5. These observations taken together reveal that RAS-MEK-ERK1/2 signaling pathway can sensitize cells to TRAIL-induced apoptosis by up-regulating DR4 and DR5 and overall imply that TRAIL-based therapeutic strategies using TRAIL agonists could be used in cases of human colon cancers bearing RAS mutations.

UR - http://www.scopus.com/inward/record.url?scp=20744450585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20744450585&partnerID=8YFLogxK

U2 - 10.1074/jbc.M412483200

DO - 10.1074/jbc.M412483200

M3 - Article

C2 - 15757891

AN - SCOPUS:20744450585

VL - 280

SP - 22856

EP - 22867

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 24

ER -