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Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling

Sanchez, Pilar
Hernandez, A. M.
Stecca, Barbara
Kahler, A. J.
DeGueme, A. M.
Barrett, Andrea
Beyna, Mercedes
Datta, M. W.
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Published in Proceedings of the National Academy of Sciences. 2004, vol. 101, no. 34, p. 12561-12566
Abstract Prostate cancer is the most common solid tumor in men, and it shares with all cancers the hallmark of elevated, nonhomeostatic cell proliferation. Here we have tested the hypothesis that the SONIC HEDGEHOG (SHH)-GLI signaling pathway is implicated in prostate cancer. We report expression of SHH-GLI pathway components in adult human prostate cancer, often with enhanced levels in tumors versus normal prostatic epithelia. Blocking the pathway with cyclopamine or anti-SHH antibodies inhibits the proliferation of GLI1+/PSA+ primary prostate tumor cultures. Inversely, SHH can potentiate tumor cell proliferation, suggesting that autocrine signaling may often sustain tumor growth. In addition, pathway blockade in three metastatic prostate cancer cell lines with cyclopamine or through GLI1 RNA interference leads to inhibition of cell proliferation, suggesting cell-autonomous pathway activation at different levels and showing an essential role for GLI1 in human cells. Our data demonstrate the dependence of prostate cancer on SHH-GLI function and suggest a novel therapeutic approach.
Keywords Cell Division/ physiologyDNA-Binding Proteins/metabolismHedgehog ProteinsHumansKruppel-Like Transcription FactorsMaleMembrane Proteins/metabolismNerve Tissue Proteins/metabolismNuclear Proteins/metabolismProstate/cytology/metabolismProstatic Neoplasms/ metabolism/pathologyRNA InterferenceReceptors, Cell SurfaceSignal Transduction/ physiologyTrans-Activators/ metabolismTranscription Factors/genetics/ metabolismTumor Cells, Cultured
PMID: 15314219
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SANCHEZ, Pilar et al. Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. In: Proceedings of the National Academy of Sciences, 2004, vol. 101, n° 34, p. 12561-12566. doi: 10.1073/pnas.0404956101 https://archive-ouverte.unige.ch/unige:9012

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Deposited on : 2010-07-12

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