Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma
Autor: | Jessica L. Bell, Andrew J. Haak, Cheryl E. Rockwell, Yajing Ji, Scott D. Larsen, Monique Verhaegen, Melanie A. Krook, Kathryn M. Appleton, Susan M. Wade, Sean A. Misek, Erika M. Lisabeth, Merlin Airik, Elizabeth R. Lawlor, Richard R. Neubig |
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Rok vydání: | 2017 |
Předmět: |
rho GTP-Binding Proteins
0301 basic medicine Cancer Research Lung Neoplasms Transcription Genetic Nipecotic Acids RhoC Gene Expression Antineoplastic Agents Biology Article Metastasis Mice 03 medical and health sciences Cell Movement Cell Line Tumor medicine Animals Humans Neoplasm Metastasis Melanoma neoplasms Transcription factor Cell Proliferation Cell Cycle Cell migration Cell cycle medicine.disease Xenograft Model Antitumor Assays Actins Disease Models Animal 030104 developmental biology Oncology rhoC GTP-Binding Protein Myocardin Immunology Disease Progression Trans-Activators Cancer research biology.protein Female RhoC GTP-Binding Protein Signal Transduction |
Zdroj: | Molecular Cancer Therapeutics. 16:193-204 |
ISSN: | 1538-8514 1535-7163 |
Popis: | Melanoma is the most dangerous form of skin cancer with the majority of deaths arising from metastatic disease. Evidence implicates Rho-activated gene transcription in melanoma metastasis mediated by the nuclear localization of the transcriptional coactivator, myocardin-related transcription factor (MRTF). Here, we highlight a role for Rho and MRTF signaling and its reversal by pharmacologic inhibition using in vitro and in vivo models of human melanoma growth and metastasis. Using two cellular models of melanoma, we clearly show that one cell type, SK-Mel-147, is highly metastatic, has high RhoC expression, and MRTF nuclear localization and activity. Conversely, SK-Mel-19 melanoma cells have low RhoC expression, and decreased levels of MRTF-regulated genes. To probe the dependence of melanoma aggressiveness to MRTF transcription, we use a previously developed small-molecule inhibitor, CCG-203971, which at low micromolar concentrations blocks nuclear localization and activity of MRTF-A. In SK-Mel-147 cells, CCG-203971 inhibits cellular migration and invasion, and decreases MRTF target gene expression. In addition, CCG-203971–mediated inhibition of the Rho/MRTF pathway significantly reduces cell growth and clonogenicity and causes G1 cell-cycle arrest. In an experimental model of melanoma lung metastasis, the RhoC-overexpressing melanoma cells (SK-Mel-147) exhibited pronounced lung colonization compared with the low RhoC–expressing SK-Mel-19. Furthermore, pharmacologic inhibition of the MRTF pathway reduced both the number and size of lung metastasis resulting in a marked reduction of total lung tumor burden. These data link Rho and MRTF-mediated signaling with aggressive phenotypes and support targeting the MRTF transcriptional pathway as a novel approach to melanoma therapeutics. Mol Cancer Ther; 16(1); 193–204. ©2016 AACR. |
Databáze: | OpenAIRE |
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