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

• Published in: The Journal of biological chemistry 2005-06, Vol.280 (24), p.22856-22867
• Main Authors: Drosopoulos, Konstantinos G, Roberts, Michael L, Cermak, Lukas, Sasazuki, Takehiko, Shirasawa, Senji, Andera, Ladislav, Pintzas, Alexander
• Format: Article
• Language: English
• Subjects: Androstadienes - pharmacology; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Cell Separation; Cell Survival; Cell Transformation, Neoplastic; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Down-Regulation; Enzyme Inhibitors - pharmacology; Flavonoids - pharmacology; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; MAP Kinase Kinase Kinases - metabolism; Membrane Glycoproteins - metabolism; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; Oncogene Protein p21(ras) - metabolism; Oncogene Protein p21(ras) - physiology; Phosphorylation; Proto-Oncogene Proteins c-fos - biosynthesis; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - biosynthesis; Reverse Transcriptase Polymerase Chain Reaction; RNA - metabolism; RNA, Messenger - metabolism; Signal Transduction; Time Factors; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - metabolism; Up-Regulation; Wortmannin
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M412483200

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.