Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis

Mohammad Athar, Chengxin Li, Xiuwei Tang, Sumin Chi, Xiaoli Zhang, Arianna L. Kim, Stephen K. Tyring, Levy Kopelovich, Jennifer Hebert, Ervin H. Epstein, David R. Bickers, Jingwu Xie

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Abnormal activation of the hedgehog-signaling pathway is the pivotal abnormality driving the growth of basal cell carcinomas (BCCs), the most common type of human cancer. Antagonists of this pathway such as cyclopamine may therefore be useful for treatment of basal cell carcinomas and other hedgehog-driven tumors. We report here that chronic oral administration of cyclopamine dramatically reduces (∼66%) UVB-induced basal cell carcinoma formation in Ptch1+/- mice. Fas expression is low in human and murine basal cell carcinomas but is up-regulated in the presence of the smoothened (SMO) antagonist, cyclopamine, both in vitro in the mouse basal cell carcinoma cell line ASZ001 and in vivo after acute treatment of mice with basal cell carcinomas. This parallels an elevated rate of apoptosis. Conversely, expression of activated SMO in C3H10T1/2 cells inhibits Fas expression. Fas/Fas ligand interactions are necessary for cyclopamine-mediated apoptosis in these cells, a process involving caspase-8 activation. Our data provide strong evidence that cyclopamine and perhaps other SMO antagonists are potent in vivo inhibitors of UVB-induced basal cell carcinomas in Ptch1+/- mice and likely in humans because the majority of human basal cell carcinomas manifest mutations in PTCH1 and that a major mechanism of their inhibitory effect is through up-regulation of Fas, which augments apoptosis.

Original languageEnglish (US)
Pages (from-to)7545-7552
Number of pages8
JournalCancer Research
Volume64
Issue number20
DOIs
StatePublished - Oct 15 2004
Externally publishedYes

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Basal Cell Carcinoma
Apoptosis
Hedgehogs
Fas Ligand Protein
Caspase 8
Oral Administration
Neoplasms
Up-Regulation
cyclopamine
Cell Line
Mutation
Therapeutics
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis. / Athar, Mohammad; Li, Chengxin; Tang, Xiuwei; Chi, Sumin; Zhang, Xiaoli; Kim, Arianna L.; Tyring, Stephen K.; Kopelovich, Levy; Hebert, Jennifer; Epstein, Ervin H.; Bickers, David R.; Xie, Jingwu.

In: Cancer Research, Vol. 64, No. 20, 15.10.2004, p. 7545-7552.

Research output: Contribution to journalArticle

Athar, M, Li, C, Tang, X, Chi, S, Zhang, X, Kim, AL, Tyring, SK, Kopelovich, L, Hebert, J, Epstein, EH, Bickers, DR & Xie, J 2004, 'Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis', Cancer Research, vol. 64, no. 20, pp. 7545-7552. https://doi.org/10.1158/0008-5472.CAN-04-1393
Athar, Mohammad ; Li, Chengxin ; Tang, Xiuwei ; Chi, Sumin ; Zhang, Xiaoli ; Kim, Arianna L. ; Tyring, Stephen K. ; Kopelovich, Levy ; Hebert, Jennifer ; Epstein, Ervin H. ; Bickers, David R. ; Xie, Jingwu. / Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of fas expression and apoptosis. In: Cancer Research. 2004 ; Vol. 64, No. 20. pp. 7545-7552.
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