A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition
| Autor: | Paul J. Higgins, R. Matthew Klein |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Proto-Oncogene Proteins B-raf
rho GTP-Binding Proteins Cancer Research RHOA Indoles Cell Survival Short Communication Recombinant Fusion Proteins Mutant Biology lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine RNA interference Cell Movement Cell Line Tumor Spheroids Cellular medicine Humans Neoplasm Invasiveness neoplasms Melanoma 030304 developmental biology 0303 health sciences Sulfonamides Rnd3 Imidazoles lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 3. Good health Clinical trial Oncology Amino Acid Substitution Drug Resistance Neoplasm 030220 oncology & carcinogenesis Gene Knockdown Techniques Cancer research biology.protein Molecular Medicine Mutant Proteins RNA Interference Signal transduction rhoA GTP-Binding Protein Signal Transduction |
| Zdroj: | Molecular Cancer Molecular Cancer, Vol 10, Iss 1, p 114 (2011) |
| ISSN: | 1476-4598 |
| Popis: | Background The initial use of BRAF targeted therapeutics in clinical trials has demonstrated encouraging responses in melanoma patients, although a rise in drug-resistant cells capable of advancing malignant disease has been described. The current study uses BRAFV600E expressing WM793 melanoma cells to derive data aimed at investigating the molecular determinant of cell invasion following treatment with clinical BRAF inhibitors. Findings Small-molecule inhibitors targeting BRAF reduced MEK1/2-ERK1/2 pathway activation and cell survival; yet, viable cell subpopulations persisted. The residual cells exhibited an elongated cell shape, prominent actin stress fibers and retained the ability to invade 3-D dermal-like microenvironments. BRAF inhibitor treatments were associated with reduced expression of RND3, an antagonist of RHOA activation, and elevated RHOA-dependent signaling. Restoration of RND3 expression or RHOA knockdown attenuated the migratory ability of residual cells without affecting overall cell survival. The invasive ability of BRAF inhibitor treated cells embedded in collagen gels was diminished following RND3 re-expression or RHOA depletion. Conversely, melanoma cell movement in the absence of BRAF inhibition was unaffected by RND3 expression or RHOA depletion. Conclusion These data reveal a novel switch in the requirement for RND3 and RHOA in coordinating the movement of residual WM793 cells that are initially refractive to BRAF inhibitor therapy. These results have important clinical implications because they suggest that combining BRAF inhibitors with therapies that target the invasion of drug-resistant cells could aid in controlling disease relapse. |
| Databáze: | OpenAIRE |
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