TY - JOUR
T1 - Endothelin-1 upregulates MCAM in melanocytes
AU - Mangahas, Catherine R
AU - dela Cruz, Gelo V
AU - Schneider, Robert J
AU - Jamal, Sumayah
PY - 2004/12
Y1 - 2004/12
N2 - Melanoma cell adhesion molecule (MCAM) is a cell-surface adhesion molecule expressed on over 70% of metastatic melanoma cells but not expressed in normal melanocytes invivo. Protein levels of MCAM correlate with aggressive invasive behavior of melanoma cells in vitro and invivo. Here we demonstrate that endothelin-1 (ET-1) upregulates MCAM protein in primary human melanocytes. MCAM upregulation by ET-1 occurs irrespective of degree of melanocyte pigmentation and is dose-responsive. The drug BQ788 is an endothelin-B (ET(B)) receptor antagonist and inhibits upregulation of MCAM by ET-1. In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM. These demonstrate a critical role for the ET(B) receptor in the upregulation of MCAM by ET-1 and related isoforms. MCAM mRNA abundance is also increased by ET-1 stimulation, thus the mechanism of MCAM protein upregulation may occur at the level of transcription. Our previous studies have demonstrated that ET-1 downregulates E-cadherin in melanocytes and melanoma cells. Since E-cadherin is a melanoma invasion suppressor, and MCAM is a melanoma invasion promoter, ET-1 may promote melanoma invasion and metastasis through the regulation of adhesion molecule expression.
AB - Melanoma cell adhesion molecule (MCAM) is a cell-surface adhesion molecule expressed on over 70% of metastatic melanoma cells but not expressed in normal melanocytes invivo. Protein levels of MCAM correlate with aggressive invasive behavior of melanoma cells in vitro and invivo. Here we demonstrate that endothelin-1 (ET-1) upregulates MCAM protein in primary human melanocytes. MCAM upregulation by ET-1 occurs irrespective of degree of melanocyte pigmentation and is dose-responsive. The drug BQ788 is an endothelin-B (ET(B)) receptor antagonist and inhibits upregulation of MCAM by ET-1. In addition, endothelin-3 (ET-3) and N-succinyl-[Glu9, Ala11, 15]-ET-1-1620, both selective ET(B) agonists, are potent upregulators of MCAM. These demonstrate a critical role for the ET(B) receptor in the upregulation of MCAM by ET-1 and related isoforms. MCAM mRNA abundance is also increased by ET-1 stimulation, thus the mechanism of MCAM protein upregulation may occur at the level of transcription. Our previous studies have demonstrated that ET-1 downregulates E-cadherin in melanocytes and melanoma cells. Since E-cadherin is a melanoma invasion suppressor, and MCAM is a melanoma invasion promoter, ET-1 may promote melanoma invasion and metastasis through the regulation of adhesion molecule expression.
KW - Antigens, CD/genetics
KW - CD146 Antigen
KW - Endothelin B Receptor Antagonists
KW - Endothelin-1/metabolism
KW - Gene Expression/drug effects
KW - Humans
KW - Kinetics
KW - Melanocytes/cytology
KW - Melanoma
KW - Neural Cell Adhesion Molecules/genetics
KW - Oligopeptides/pharmacology
KW - Piperidines/pharmacology
KW - RNA, Messenger/metabolism
KW - Skin Neoplasms
KW - Tumor Cells, Cultured
KW - Up-Regulation/drug effects
U2 - 10.1111/j.0022-202X.2004.23480.x
DO - 10.1111/j.0022-202X.2004.23480.x
M3 - Journal article
C2 - 15610525
SN - 0022-202X
VL - 123
SP - 1135
EP - 1139
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 6
ER -