IFNalpha induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling.
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 IFNalpha mediates apoptosis in BCCs. In the presence of IFNalpha, 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 IFNalpha in sonic hedgehog responsive C3H10T1/2 cells. In transient transfection experiments, we demonstrate that IFNalpha inhibits Erk phosphorylation and serum response element activation induced by expression of SMO, Gli1, PDGFRalpha and activated Raf, but not activated mitogen-activated Erk-regulating kinase (Mek), suggesting that IFNalpha targets mainly on Mek function. We further show that IFNalpha induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in IFNalpha-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFNalpha-mediated apoptosis. Thus, our data indicate that IFNalpha-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function.
Li
Chengxin
C
Sealy Center for Cancer Cell Biology, Department of Pharmacology and Toxicology, University of Texas Medical Branch at Galveston, TX 77555, USA.
Chi
Sumin
S
He
Nonggao
N
Zhang
Xiaoli
X
Guicherit
Oivin
O
Wagner
Richard
R
Tyring
Stephen
S
Xie
Jingwu
J
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival; D004789:Enzyme Activation; D053823:Hedgehog Proteins; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*; D018631:ras Proteins / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; D016898:Interferon-alpha; C509239:SHH protein, human; D015534:Trans-Activators; D019014:fas Receptor; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins