The aryl hydrocarbon receptor mediates leflunomide-induced growth inhibition of melanoma cells
| Autor: | Nancy I. Kerkvliet, Edmond F. O’Donnell, Prasad Rao Kopparapu, Hyo Sang Jang, Robert L. Tanguay, Siva Kumar Kolluri, Daniel C. Koch, Jessica Lynne Phillips |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Melanomas
Skin Neoplasms Dihydroorotate Dehydrogenase Cancer Treatment lcsh:Medicine Hydroxybutyrates Toxicology Biochemistry chemistry.chemical_compound 0302 clinical medicine Drug Metabolism Immunotoxicology Molecular Cell Biology lcsh:Science Melanoma Leflunomide 0303 health sciences Multidisciplinary Aniline Compounds biology Fluoresceins 3. Good health Oncology 030220 oncology & carcinogenesis Crotonates Gene Knockdown Techniques Medicine Oncology Agents Growth inhibition medicine.drug Signal Transduction Research Article Cyclin-Dependent Kinase Inhibitor p21 Oxidoreductases Acting on CH-CH Group Donors Drugs and Devices Drug Research and Development Toluidines Immunology Succinimides Malignant Skin Neoplasms Dermatology Cell Growth Proto-Oncogene Proteins c-myc Immunomodulation 03 medical and health sciences Cell Line Tumor Nitriles medicine Humans Pharmacokinetics Uridine Biology 030304 developmental biology Cell Proliferation Cell growth lcsh:R Isoxazoles Aryl hydrocarbon receptor chemistry Receptors Aryl Hydrocarbon Cell culture Cancer cell biology.protein Cancer research Dihydroorotate dehydrogenase lcsh:Q Clinical Immunology |
| Zdroj: | PLoS ONE PLoS ONE, Vol 7, Iss 7, p e40926 (2012) |
| ISSN: | 1932-6203 |
| Popis: | A novel role of the dihydroorotatedehydrogenase (DHODH) inhibitor leflunomide as a potential anti-melanoma therapy was recently reported (Nature 471:518-22, 2011). We previously reported that leflunomide strongly activates the transcriptional activity of the Aryl Hydrocarbon Receptor (AhR). We therefore tested whether the AhR regulates the anti-proliferative effects of leflunomide in melanoma. We first evaluated the expression of AhR in melanoma cells and found that AhR is highly expressed in A375 melanoma as well as in several other cancer cell types. To evaluate whether AhR plays a role in regulating the growth inhibitory effects of leflunomide in A375 cells, we generated a stable cell line from parental A375 cells expressing a doxycycline (DOX) inducible AhR shRNA. Using these cells in the absence or presence of DOX (normal AhR levels or AhR-knockdown, respectively) we found that the anti-proliferative effects of leflunomide, but not its metabolite A771726, were strongly dependent upon AhR expression. It has been well established that supplementation of cells with exogenous uridine completely rescues the anti-proliferative effects due to DHODH inhibition. Thus, we performed uridine rescue experiments in A375 cells to determine whether the anti-proliferative effects of leflunomide are solely due to DHODH inhibition as previously reported. Interestingly, saturating levels of uridine only modestly rescued A375 cells from the anti-proliferative effects of both leflunomide and A771726, indicating additional mechanism(s), apart from DHODH inhibition are responsible for the anti-proliferative effects of leflunomide in melanoma cells. Uridine also did not rescue MDA-MB-435S melanoma cell proliferation after leflunomide treatment. Our results reveal that the AhR is a molecular target of leflunomide and support the feasibility of the clinical application of leflunomide for treating melanoma. Furthermore, analysis of expression data from 967 cancer cell lines revealed that AhR is expressed in multiple different cancer types supporting the intriguing possibility of targeting the AhR for therapy in a number of cancers. |
| Databáze: | OpenAIRE |
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