Pharmacological Inhibition of Myocardin-related Transcription Factor Pathway Blocks Lung Metastases of RhoC-Overexpressing Melanoma.
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 G1cell-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.
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan.
Andrew J
AJ
Haak
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan.
Kathryn M
KM
Appleton
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan.
Erika M
EM
Lisabeth
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan.
Sean A
SA
Misek
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan.
Yajing
Y
Ji
Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan.
Susan M
SM
Wade
Department of Medicinal Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan.|College of Pharmacy, University of Michigan Medical Center, Ann Arbor, Michigan.
Jessica L
JL
Bell
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan.
Cheryl E
CE
Rockwell
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan.
Merlin
M
Airik
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan.
Melanie A
MA
Krook
Department of Medicinal Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan.|College of Pharmacy, University of Michigan Medical Center, Ann Arbor, Michigan.
Scott D
SD
Larsen
Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan.
Monique
M
Verhaegen
Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan.
Elizabeth R
ER
Lawlor
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, Michigan. RNeubig@msu.edu.
Richard R
RR
Neubig
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D009557:Nipecotic Acids / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays; D020741:rho GTP-Binding Proteins / Q000235:genetics*; D000075024:rhoC GTP-Binding Protein
D000199:Actins; D000970:Antineoplastic Agents; C431575:MRTFA protein, human; C000589288:N-(4-chlorophenyl)-1-((3-(furan-2-yl)phenyl)carbonyl)piperidine-3-carboxamide; D009557:Nipecotic Acids; D015534:Trans-Activators; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein