Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells: role of BRAF mutation and fibroblast growth factor signaling.
Melanoma progresses as a multistep process where the thickness of the lesion and depth of tumor invasion are the best prognostic indicators of clinical outcome. Degradation of the interstitial collagens in the extracellular matrix is an integral component of tumor invasion and metastasis, and much of this degradation is mediated by collagenase-1 (MMP-1), a member of the matrix metalloproteinase (MMP) family. MMP-1 levels increase during melanoma progression where they are associated with shorter disease-free survival. The Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is a major regulator of melanoma cell proliferation. Recently, BRAF has been identified as a common site of activating mutations, and, although many reports focus on its growth-promoting effects, this pathway has also been implicated in progression toward metastatic disease. In this study, we describe four melanoma cell lines that produce high levels of MMP-1 constitutively. In each cell line the Ras/Raf/MEK/ERK pathway is constitutively active and is the dominant pathway driving the production of MMP-1. Activation of this pathway arises due to either an activating mutation in BRAF (three cell lines) or autocrine fibroblast growth factor signaling (one cell line). Furthermore, blocking MEK/ERK activity inhibits melanoma cell proliferation and abrogates collagen degradation, thus decreasing their metastatic potential. Importantly, this inhibition of invasive behavior can occur in the absence of any detectable changes in cell proliferation and survival. Thus, constitutive activation of this MAPK pathway not only promotes the increased proliferation of melanoma cells but is also important for the acquisition of an invasive phenotype.
Huntington
Jonathan T
JT
Norris Cotton Cancer Center, Departments of Physiology, Medicine, and Biochemistry, Dartmouth Medical School, Lebanon NH 03756, USA.
Shields
Janiel M
JM
Der
Channing J
CJ
Wyatt
Colby A
CA
Benbow
Ulrike
U
Slingluff
Craig L
CL
Brinckerhoff
Constance E
CE
D018053:Arsenites / Q000494:pharmacology; D018572:Disease-Free Survival; D004789:Enzyme Activation / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020781:Matrix Metalloproteinase 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D017670:Sodium Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018053:Arsenites; D012333:RNA, Messenger; D017670:Sodium Compounds; C017947:sodium arsenite; D005346:Fibroblast Growth Factors; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020781:Matrix Metalloproteinase 1