title: The BRAF(V600E) inhibitor, PLX4032, increases type I collagen synthesis in melanoma cells.
abstract: Vertical growth phase (VGP) melanoma is frequently metastatic, a process mediated by changes in gene expression, which are directed by signal transduction pathways in the tumor cells. A prominent signaling pathway is the Ras-Raf-Mek-Erk MAPK pathway, which increases expression of genes that promote melanoma progression. Many melanomas harbor a mutation in this pathway, BRAF(V600E), which constitutively activates MAPK signaling and expression of downstream target genes that facilitate tumor progression. In BRAF(V600E) melanoma, the small molecule inhibitor, vemurafenib (PLX4032), has revolutionized therapy for melanoma by inducing rapid tumor regression. This compound down-regulates the expression of many genes. However, in this study, we document that blocking the Ras-Raf-Mek-Erk MAPK pathway, either with an ERK (PLX4032) or a MEK (U1026) signaling inhibitor, in BRAF(V600E) human and murine melanoma cell lines increases collagen synthesis in vitro and collagen deposition in vivo. Since TGFß signaling is a major mediator of collagen synthesis, we examined whether blocking TGFß signaling with a small molecule inhibitor would block this increase in collagen. However, there was minimal reduction in collagen synthesis in response to blocking TGFß signaling, suggesting additional mechanism(s), which may include activation of the p38 MAPK pathway. Presently, it is unclear whether this increased collagen synthesis and deposition in melanomas represent a therapeutic benefit or an unwanted "off target" effect of inhibiting the Ras-Raf-Erk-Mek pathway.
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States; Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States. Electronic address: Molly.H.Jenkins@dartmouth.edu.
authors.forename: Molly H
authors.initials: MH
authors.lastname: Jenkins
authors.affiliation: Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States.
authors.forename: Walburga
authors.initials: W
authors.lastname: Croteau
authors.affiliation: Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Mullins
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States; Department of Biochemistry, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States.
authors.forename: Constance E
authors.initials: CE
authors.lastname: Brinckerhoff
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D024042:Collagen Type I; D007211:Indoles; C528407:PLX 4720; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins
keywords: Human melanoma; IL-8; MMP-1; Murine melanoma; TGFβ; Vemurafenib; pERK