| Autor: |
Chengxin Li, Colin S., Sumin Chi, Colin S., Nonggao He, Colin S., Xiaoli Zhang, Oivin Guicherit, Colin S., Wagner, Richard, Tyring, Stephen, Jingwu Xie |
| Předmět: |
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| Zdroj: |
Oncogene; 2/26/2004, Vol. 23 Issue 8, p1608-1617, 10p, 3 Color Photographs, 6 Black and White Photographs, 4 Diagrams, 5 Graphs |
| Abstrakt: |
Basal cell carcinoma (BCC), the most common form of human cancer, is understood to be associated with activation of the sonic hedgehog pathway, through loss-of-function mutations of tumor suppressor PTCH1 or gain-of-function mutations of smoothened. Interferon (IFN)-based therapy is quite effective in BCC treatment, but the molecular basis is not well understood. Here we report a novel mechanism by which IFNa mediates apoptosis in BCCs. In the presence of IFNa, we observed increased apoptosis in a BCC cell line ASZ001, in which PTC is null, and therefore with constitutive activation of the sonic hedgehog pathway. We demonstrate that SMO agonist Ag-1.4 mediates activation of extracellular signal-regulated kinase (Erk) phosphorylation, which is abrogated by IFNa in sonic hedgehog responsive C3H10T1/2 cells. In transient transfection experiments, we demonstrate that IFNa inhibits Erk phosphorylation and serum response element activation induced by expression of SMO, Gli1, PDGFRa and activated Raf, but not activated mitogen-activated Erk-regulating kinase (Mek), suggesting that IFNa targets mainly on Mek function. We further show that IFNa induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in IFNa-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFNa-mediated apoptosis. Thus, our data indicate that IFNa-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function.Oncogene (2004) 23, 1608-1617. doi:10.1038/sj.onc.1207273 Published online 1 December 2003 [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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