Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling.
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.
Skirball Institute and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Pilar
P
Sanchez
Ana Maria
AM
Hernández
Barbara
B
Stecca
Andrea J
AJ
Kahler
Amy M
AM
DeGueme
Andrea
A
Barrett
Mercedes
M
Beyna
Milton W
MW
Datta
Sumana
S
Datta
Ariel
A
Ruiz i Altaba
D002455:Cell Division / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D000072079:Patched Receptors; D011467:Prostate / Q000166:cytology / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
D004268:DNA-Binding Proteins; C400551:GLI1 protein, human; C082593:GLI2 protein, human; C065683:GLI3 protein, human; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3