title: Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists.
abstract: The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Novum Research Park, Hälsovägen 7, SE-141 57 Huddinge, Sweden.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
authors.forename: Asa
authors.initials: A
authors.lastname: Bergström
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimokawa
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002460:Cell Line; D004273:DNA, Neoplasm / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014183:Transplantation, Heterologous; D000071676:Zinc Finger Protein GLI1
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1