Abstract
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 IFNα mediates apoptosis in BCCs. In the presence of IFNα, 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 IFNα in sonic hedgehog responsive C3H10T1/2 cells. In transient transfection experiments, we demonstrate that IFNα inhibits Erk phosphorylation and serum response element activation induced by expression of SMO, Gli1, PDGFRα and activated Raf, but not activated mitogen-activated Erk-regulating kinase (Mek), suggesting that IFNα targets mainly on Mek function. We further show that IFNα induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in IFNα-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFNα-mediated apoptosis. Thus, our data indicate that IFNα-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function.
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Acknowledgements
We thank Drs Ervin Epstein and Michelle Aszterbaum for providing reagents and members of the Sealy Center for Cancer Cell Biology for discussion. This study was supported by an R01 grant from NCI (JX), the NIEHS center (JX) and John Sealy Memorial Endowment Fund for Biomedical Research (JX).
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Li, C., Chi, S., He, N. et al. IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling. Oncogene 23, 1608–1617 (2004). https://doi.org/10.1038/sj.onc.1207273
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DOI: https://doi.org/10.1038/sj.onc.1207273
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