Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells

Mario Anders; Christine Christian; Martin McMahon; Frank McCormick; W Michael Korn

Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells

Standard

Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells. / Anders, Mario; Christian, Christine; McMahon, Martin; McCormick, Frank; Korn, W Michael.

In: CANCER RES, Vol. 63, No. 9, 01.05.2003, p. 2088-95.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Anders, M, Christian, C, McMahon, M, McCormick, F & Korn, WM 2003, 'Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells', CANCER RES, vol. 63, no. 9, pp. 2088-95.

APA

Anders, M., Christian, C., McMahon, M., McCormick, F., & Korn, W. M. (2003). Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells. CANCER RES, 63(9), 2088-95.

Vancouver

Anders M, Christian C, McMahon M, McCormick F, Korn WM. Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells. CANCER RES. 2003 May 1;63(9):2088-95.

Bibtex

@article{4c5ab922c4444677979808d06d653dc3,

title = "Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells",

abstract = "Recombinant adenoviruses are presently being tested clinically as a new strategy for the treatment of cancer. An important determining factor for the successful entry of such adenoviruses into target cells is expression of the coxsackievirus and adenovirus receptor (CAR) at the cell surface. Recent observations suggest that expression of this receptor, which physiologically participates in formation of cell-cell adhesions, is frequently reduced in highly malignant cancer cells. This raises the possibility that those tumors representing the greatest therapeutic challenge might be the least susceptible to infection with therapeutic adenoviruses. We explored the role of the Raf-MEK-ERK pathway on CAR expression in a panel of cancer cells because this pathway is frequently up-regulated in cancer cells and is known to down-regulate cell-cell adhesion molecules. We found that disruption of signaling through the Raf-MEK-ERK pathway by inhibition of MEK up-regulated CAR expression, which was accompanied by increased representation of the protein at the cell surface. After Raf-MEK-ERK inhibition, adenovirus entry into cells was increased and cell killing by replication competent adenoviruses was enhanced in a CAR-dependent manner. Conversely, induction of Raf-1 resulted in reduction and disruption of CAR expression at the cell surface. We conclude that loss of CAR expression in cancer cells is, at least in part, mediated through the Raf-MEK-ERK signal transduction pathway and that pharmacological restoration of CAR at the cell surface could improve adenovirus-based treatments of cancer.",

keywords = "Adenoviruses, Human, Animals, Cell Membrane, Colorectal Neoplasms, Coxsackie and Adenovirus Receptor-Like Membrane Protein, Dogs, Enzyme Inhibitors, G1 Phase, Gene Expression Regulation, Neoplastic, Green Fluorescent Proteins, Humans, Luminescent Proteins, MAP Kinase Kinase Kinase 1, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinases, Pancreatic Neoplasms, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-raf, Receptors, Virus, Recombinant Fusion Proteins, Transcriptional Activation, Tumor Cells, Cultured, Up-Regulation",

author = "Mario Anders and Christine Christian and Martin McMahon and Frank McCormick and Korn, {W Michael}",

year = "2003",

month = may,

day = "1",

language = "English",

volume = "63",

pages = "2088--95",

journal = "CANCER RES",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "9",

}

RIS

TY - JOUR

T1 - Inhibition of the Raf/MEK/ERK pathway up-regulates expression of the coxsackievirus and adenovirus receptor in cancer cells

AU - Anders, Mario

AU - Christian, Christine

AU - McMahon, Martin

AU - McCormick, Frank

AU - Korn, W Michael

PY - 2003/5/1

Y1 - 2003/5/1

N2 - Recombinant adenoviruses are presently being tested clinically as a new strategy for the treatment of cancer. An important determining factor for the successful entry of such adenoviruses into target cells is expression of the coxsackievirus and adenovirus receptor (CAR) at the cell surface. Recent observations suggest that expression of this receptor, which physiologically participates in formation of cell-cell adhesions, is frequently reduced in highly malignant cancer cells. This raises the possibility that those tumors representing the greatest therapeutic challenge might be the least susceptible to infection with therapeutic adenoviruses. We explored the role of the Raf-MEK-ERK pathway on CAR expression in a panel of cancer cells because this pathway is frequently up-regulated in cancer cells and is known to down-regulate cell-cell adhesion molecules. We found that disruption of signaling through the Raf-MEK-ERK pathway by inhibition of MEK up-regulated CAR expression, which was accompanied by increased representation of the protein at the cell surface. After Raf-MEK-ERK inhibition, adenovirus entry into cells was increased and cell killing by replication competent adenoviruses was enhanced in a CAR-dependent manner. Conversely, induction of Raf-1 resulted in reduction and disruption of CAR expression at the cell surface. We conclude that loss of CAR expression in cancer cells is, at least in part, mediated through the Raf-MEK-ERK signal transduction pathway and that pharmacological restoration of CAR at the cell surface could improve adenovirus-based treatments of cancer.

AB - Recombinant adenoviruses are presently being tested clinically as a new strategy for the treatment of cancer. An important determining factor for the successful entry of such adenoviruses into target cells is expression of the coxsackievirus and adenovirus receptor (CAR) at the cell surface. Recent observations suggest that expression of this receptor, which physiologically participates in formation of cell-cell adhesions, is frequently reduced in highly malignant cancer cells. This raises the possibility that those tumors representing the greatest therapeutic challenge might be the least susceptible to infection with therapeutic adenoviruses. We explored the role of the Raf-MEK-ERK pathway on CAR expression in a panel of cancer cells because this pathway is frequently up-regulated in cancer cells and is known to down-regulate cell-cell adhesion molecules. We found that disruption of signaling through the Raf-MEK-ERK pathway by inhibition of MEK up-regulated CAR expression, which was accompanied by increased representation of the protein at the cell surface. After Raf-MEK-ERK inhibition, adenovirus entry into cells was increased and cell killing by replication competent adenoviruses was enhanced in a CAR-dependent manner. Conversely, induction of Raf-1 resulted in reduction and disruption of CAR expression at the cell surface. We conclude that loss of CAR expression in cancer cells is, at least in part, mediated through the Raf-MEK-ERK signal transduction pathway and that pharmacological restoration of CAR at the cell surface could improve adenovirus-based treatments of cancer.

KW - Adenoviruses, Human

KW - Animals

KW - Cell Membrane

KW - Colorectal Neoplasms

KW - Coxsackie and Adenovirus Receptor-Like Membrane Protein

KW - Dogs

KW - Enzyme Inhibitors

KW - G1 Phase

KW - Gene Expression Regulation, Neoplastic

KW - Green Fluorescent Proteins

KW - Humans

KW - Luminescent Proteins

KW - MAP Kinase Kinase Kinase 1

KW - MAP Kinase Signaling System

KW - Mice

KW - Mitogen-Activated Protein Kinases

KW - Pancreatic Neoplasms

KW - Phosphorylation

KW - Protein-Serine-Threonine Kinases

KW - Proto-Oncogene Proteins c-raf

KW - Receptors, Virus

KW - Recombinant Fusion Proteins

KW - Transcriptional Activation

KW - Tumor Cells, Cultured

KW - Up-Regulation

M3 - SCORING: Journal article

C2 - 12727824

VL - 63

SP - 2088

EP - 2095

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 9

ER -