the aryl hydrocarbon receptor mediates leflunomide-induced growth inhibition of melanoma cells芳基碳氢化合物受体介导leflunomide-induced黑色素瘤细胞的生长抑制.pdfVIP

The Aryl Hydrocarbon Receptor Mediates Leflunomide- Induced Growth Inhibition of Melanoma Cells Edmond F. O’Donnell1,2,5, Prasad Rao Kopparapu1,2,5, Daniel C. Koch1,2,5, Hyo Sang Jang1,2,5, Jessica Lynne Phillips1,3,5, Robert L. Tanguay2,3,4,5, Nancy I. Kerkvliet2,4,5, Siva Kumar Kolluri1,2,3,4,5* 1 Cancer Research Laboratory, Oregon State University, Corvallis, Oregon, United States of America, 2 Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, United States of America, 3 Molecular and Cellular Biology Program, Oregon State University, Corvallis, Oregon, United States of America, 4 Environmental Health Sciences Center, Oregon State University, Corvallis, Oregon, United States of America, 5 Oregon State University, Corvallis, Oregon, United States of America Abstract 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