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 IFN_α_ mediates apoptosis in BCCs. In the presence of IFN_α_, 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)

targets mainly on Mek function. We further show that IFN_α_ induces expression of Fas in BCC cells through interfering with Mek function. The role of the Fas-L/Fas signaling axis in

IFN_α_-mediated apoptosis is demonstrated by the fact that addition of Fas-L neutralizing antibodies, just as caspase-8 inhibitor Z-IETD-FMK, effectively prevents IFN_α_-mediated apoptosis.

Thus, our data indicate that IFN_α_-based BCC therapy induces Fas expression and apoptosis through interfering with Mek function. Access through your institution Buy or subscribe This is a

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COOPERATIVITY DRIVES NON-CANONICAL HEDGEHOG SIGNALING IN RESISTANT BASAL CELL CARCINOMA Article Open access 08 October 2020 MAPK-NEGATIVE FEEDBACK REGULATION CONFERS DEPENDENCE TO JAK2V617F

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Bare J, Rothman A, Collins C, Cutone S, Rutter M, McCormick MK and Epstein Jr E . (1997b). _Genes Chromosomes Cancer_, 18, 305–309. Download references 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). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pharmacology and Toxicology, Sealy Center

for Cancer Cell Biology, University of Texas Medical Branch at Galveston, 77555, TX, USA Chengxin Li, Sumin Chi, Nonggao He, Xiaoli Zhang & Jingwu Xie * Curis, Inc., 6, 1 Moulton Street,

Cambridge, 02138, MA, USA Oivin Guicherit * Department of Dermatology, University of Texas Medical Branch at Galveston, 77555, TX, USA Richard Wagner & Stephen Tyring * Department of

Dermatology, Xijing Hospital, Xi'an, 710032, China Chengxin Li * Departments of Microbiology and Immunology, University of Texas Medical Branch at Galveston, 77555, TX, USA Stephen

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ARTICLE Li, C., Chi, S., He, N. _et al._ IFN_α_ 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 Download citation * Received: 18 May 2003 * Revised: 16 August 2003 * Accepted: 10 October 2003 * Published: 01 December 2003 * Issue Date: 26

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shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * hedgehog * smoothened * BCCs *

PDGFR_α_ * INF_α_ * MEK * Fas