Journal
CHEMBIOCHEM
Volume 9, Issue 7, Pages 1082-1092Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.200700511
Keywords
GLI; hedgehog; inhibitors; natural products
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The aberrant hedgehog (Hh)/GLI signaling pathway causes the formation and progression of a variety of tumors. To search for Hh/GLI inhibitors, we screened for naturally occurring inhibitors of the transcriptional activator GLI1 by using a cell-based assay. We identified zerumbone (1), zerumbone epoxide (2), staurosporinone (9), 6-hydroxystourosporinone (10), orcyriaflavin C (71) and 5,6-dihydroxyarcyrioflovin A (12) as inhibitors of GLI-mediated transcription. In addition, we isolated physolins F (17) and B (18) from Physalis minima, which are also potent inhibitors. These compounds also inhibited GLI2-mediated transactivation. Semiquantitative RT-PCR and Western blotting analysis further revealed that 1, 9, 17, and 18 decreased Hh-related component expressions. We also show that inhibitors of GLI-mediated transactivation reduce the level of the antiapoptosis BcI2 expression. Finally, these identified compounds were cytotoxic to PANC1 pancreatic cancer cells, which express Hh/GLI components. These results strongly suggest that the cytotoxicity of the compounds to PANC1 cells correlates with their inhibition of GLI-mediated transcription.
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