The BRAF(V600E) inhibitor, PLX4032, increases type I collagen synthesis in melanoma cells

• Published in: Matrix biology 2015-10, Vol.48, p.66-77
• Main Authors: Jenkins, Molly H, Croteau, Walburga, Mullins, David W, Brinckerhoff, Constance E
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Collagen Type I - agonists; Collagen Type I - genetics; Collagen Type I - metabolism; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Humans; Indoles - pharmacology; MAP Kinase Signaling System; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Mitogen-Activated Protein Kinase Kinases - genetics; Mitogen-Activated Protein Kinase Kinases - metabolism; Mutation; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; raf Kinases - genetics; raf Kinases - metabolism; ras Proteins - genetics; ras Proteins - metabolism; Skin Neoplasms - drug therapy; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Sulfonamides - pharmacology; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1569-1802
• DOI: 10.1016/j.matbio.2015.05.007

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.