IFNα induces Fas expression and apoptosis in hedgehog pathway activated BCC cells through inhibiting Ras-Erk signaling

Chengxin Li, Sumin Chi, Nonggao He, Xiaoli Zhang, Oivin Guicherit, Richard Wagner, Stephen Tyring, Jingwu Xie

Research output: Contribution to journalArticle

50 Scopus citations

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 IFNa 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.

Original languageEnglish (US)
Pages (from-to)1608-1617
Number of pages10
JournalOncogene
Volume23
Issue number8
DOIs
StatePublished - Feb 26 2004
Externally publishedYes

Keywords

  • BCCs
  • FAs
  • Hedgehog
  • INFα
  • MEK
  • PDGFRα
  • Smoothened

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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