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Naturally Occurring Small‐Molecule Inhibitors of Hedgehog/GLI‐Mediated Transcription
Author(s) -
Hosoya Takahiro,
Arai Midori A.,
Koyano Takashi,
Kowithayakorn Thaworn,
Ishibashi Masami
Publication year - 2008
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200700511
Subject(s) - gli1 , transactivation , vismodegib , hedgehog signaling pathway , hedgehog , gli2 , chemistry , cytotoxicity , transcription factor , microbiology and biotechnology , transcription (linguistics) , biology , cancer research , signal transduction , biochemistry , gene , in vitro , linguistics , philosophy
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‐hydroxystaurosporinone ( 10 ), arcyriaflavin C ( 11 ) and 5,6‐dihydroxyarcyriaflavin A ( 12 ) as inhibitors of GLI‐mediated transcription. In addition, we isolated physalins 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 Bcl2 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.