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PMID: 15314219 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 34 ·2004-08-24 ·Pages 12561-6

Sanchez P, Hernández AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A, Beyna M, Datta MW, Datta S, Ruiz i Altaba A

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.

MeSH Terms
Cell Division/physiology DNA-Binding Proteins/metabolism Hedgehog Proteins Humans Kruppel-Like Transcription Factors Male Membrane Proteins/metabolism Nerve Tissue Proteins/metabolism Nuclear Proteins/metabolism Patched Receptors Prostate/cytology,metabolism Prostatic Neoplasms/metabolism,pathology RNA Interference Receptors, Cell Surface Signal Transduction/physiology Trans-Activators/metabolism Transcription Factors/genetics,metabolism Tumor Cells, Cultured Zinc Finger Protein GLI1 Zinc Finger Protein Gli2 Zinc Finger Protein Gli3
Chemicals
DNA-Binding Proteins GLI1 protein, human GLI2 protein, human GLI3 protein, human Hedgehog Proteins Kruppel-Like Transcription Factors Membrane Proteins Nerve Tissue Proteins Nuclear Proteins Patched Receptors Receptors, Cell Surface SHH protein, human Trans-Activators Transcription Factors Zinc Finger Protein GLI1 Zinc Finger Protein Gli2 Zinc Finger Protein Gli3
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sanchez Pilar
Skirball Institute and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Hernández Ana Maria
Stecca Barbara
Kahler Andrea J
DeGueme Amy M
Barrett Andrea
Beyna Mercedes
Datta Milton W
Datta Sumana
Ruiz i Altaba Ariel
References (62)
62 references, click to expand
  1. Gli and hedgehog in cancer: tumours, embryos and stem cells.
    Nat Rev Cancer. 2002 May;2(5):361-72 PMID: 12044012
  2. The LNCaP cell line--a new model for studies on human prostatic carcinoma.
    Prog Clin Biol Res. 1980;37:115-32 PMID: 7384082
  3. Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families.
    Prostate. 2003 Dec 1;57(4):320-5 PMID: 14601028
  4. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.
    Cell. 1996 Jun 14;85(6):841-51 PMID: 8681379
  5. Sonic hedgehog regulates prostatic growth and epithelial differentiation.
    Dev Biol. 2003 Dec 15;264(2):352-62 PMID: 14651923
  6. Stem cell features of benign and malignant prostate epithelial cells.
    J Urol. 1998 Dec;160(6 Pt 2):2381-92 PMID: 9817389
  7. Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.
    Cancer Res. 1997 Jul 1;57(13):2581-5 PMID: 9205058
  8. Pathological and molecular aspects of prostate cancer.
    Lancet. 2003 Mar 15;361(9361):955-64 PMID: 12648986
  9. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis.
    Dev Biol. 2004 Mar 15;267(2):387-98 PMID: 15013801
  10. Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation.
    Development. 2000 Apr;127(8):1593-605 PMID: 10725236
  11. Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation.
    Dev Biol. 2002 Sep 15;249(2):349-66 PMID: 12221011
  12. Current strategies in the management of hormone refractory prostate cancer.
    Cancer Treat Rev. 2003 Jun;29(3):171-87 PMID: 12787712
  13. Molecular genetics of prostate cancer.
    Genes Dev. 2000 Oct 1;14(19):2410-34 PMID: 11018010
  14. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours.
    Nature. 2003 Oct 23;425(6960):846-51 PMID: 14520411
  15. In vitro human cell culture models for the study of prostate cancer.
    Prostate Cancer Prostatic Dis. 2000 Dec;3(4):229-235 PMID: 12497069
  16. Expression of the PTCH1 tumor suppressor gene is regulated by alternative promoters and a single functional Gli-binding site.
    Gene. 2004 Apr 14;330:101-14 PMID: 15087129
  17. Human homolog of patched, a candidate gene for the basal cell nevus syndrome.
    Science. 1996 Jun 14;272(5268):1668-71 PMID: 8658145
  18. Hedgehog--Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer.
    Cancer Lett. 2004 Feb 20;204(2):145-57 PMID: 15013214
  19. Role of the basal cells in premalignant changes of the human prostate: a stem cell concept for the development of prostate cancer.
    Eur Urol. 1996;30(2):201-5 PMID: 8875201
  20. Conservation of the hedgehog/patched signaling pathway from flies to mice: induction of a mouse patched gene by Hedgehog.
    Genes Dev. 1996 Feb 1;10(3):301-12 PMID: 8595881
  21. Drosophila perlecan modulates FGF and hedgehog signals to activate neural stem cell division.
    Dev Biol. 2003 Jan 15;253(2):247-57 PMID: 12645928
  22. Analysis of PTCH/SMO/SHH pathway genes in medulloblastoma.
    Genes Chromosomes Cancer. 2000 Jan;27(1):44-51 PMID: 10564585
  23. Identification of PATCHED mutations in medulloblastomas by direct sequencing.
    Hum Mutat. 2000 Jul;16(1):89-90 PMID: 10874314
  24. Hedgehog signaling in animal development: paradigms and principles.
    Genes Dev. 2001 Dec 1;15(23):3059-87 PMID: 11731473
  25. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity.
    Cell. 1996 Nov 15;87(4):661-73 PMID: 8929535
  26. Prostate carcinoma: tissue culture cell lines.
    Natl Cancer Inst Monogr. 1978 Dec;(49):17-21 PMID: 571045
  27. Medulloblastoma growth inhibition by hedgehog pathway blockade.
    Science. 2002 Aug 30;297(5586):1559-61 PMID: 12202832
  28. Isolation of a human prostate carcinoma cell line (DU 145).
    Int J Cancer. 1978 Mar 15;21(3):274-81 PMID: 631930
  29. Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma.
    Oncogene. 2002 Aug 15;21(36):5529-39 PMID: 12165851
  30. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer.
    Nature. 2003 Mar 20;422(6929):313-7 PMID: 12629553
  31. Independent origin of multiple foci of prostatic intraepithelial neoplasia: comparison with matched foci of prostate carcinoma.
    Cancer. 1998 Nov 1;83(9):1995-2002 PMID: 9806659
  32. The Sonic Hedgehog-Gli pathway regulates dorsal brain growth and tumorigenesis.
    Development. 2001 Dec;128(24):5201-12 PMID: 11748155
  33. Sporadic medulloblastomas contain PTCH mutations.
    Cancer Res. 1997 Mar 1;57(5):842-5 PMID: 9041183
  34. Activation of the transcription factor Gli1 and the Sonic hedgehog signalling pathway in skin tumours.
    Nature. 1997 Oct 23;389(6653):876-81 PMID: 9349822
  35. Prostate development requires Sonic hedgehog expressed by the urogenital sinus epithelium.
    Dev Biol. 1999 May 1;209(1):28-39 PMID: 10208740
  36. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis.
    Nature. 2003 Oct 23;425(6960):851-6 PMID: 14520413
  37. Patched and smoothened mRNA expression in human astrocytic tumors inversely correlates with histological malignancy.
    J Neurooncol. 2002 Sep;59(2):107-15 PMID: 12241103
  38. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model.
    Prostate. 2003 May 15;55(3):219-37 PMID: 12692788
  39. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary.
    Nature. 2001 Mar 29;410(6828):599-604 PMID: 11279500
  40. Where are the prostate cancer genes?--A summary of eight genome wide searches.
    Prostate. 2003 Dec 1;57(4):261-9 PMID: 14601022
  41. Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system.
    Cancer Res. 1998 May 1;58(9):1798-803 PMID: 9581815
  42. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome.
    Nat Med. 1998 May;4(5):619-22 PMID: 9585239
  43. Prostate cancer.
    N Engl J Med. 2003 Jul 24;349(4):366-81 PMID: 12878745
  44. Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells.
    J Biol Chem. 2003 May 16;278(20):18506-13 PMID: 12626524
  45. Gli1 can rescue the in vivo function of Gli2.
    Development. 2001 Dec;128(24):5161-72 PMID: 11748151
  46. Simple, inexpensive method for automating tissue microarray production provides enhanced microarray reproducibility.
    Appl Immunohistochem Mol Morphol. 2003 Sep;11(3):269-73 PMID: 12966355
  47. Stem cells, cancer, and cancer stem cells.
    Nature. 2001 Nov 1;414(6859):105-11 PMID: 11689955
  48. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development.
    Development. 1997 Jul;124(13):2537-52 PMID: 9216996
  49. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched.
    Cancer Res. 1997 Jun 1;57(11):2085-8 PMID: 9187099
  50. Prediction of central nervous system embryonal tumour outcome based on gene expression.
    Nature. 2002 Jan 24;415(6870):436-42 PMID: 11807556
  51. The human prostate expresses sonic hedgehog during fetal development.
    J Urol. 2002 Nov;168(5):2206-10 PMID: 12394760
  52. The magnitude of hedgehog signaling activity defines skin tumor phenotype.
    EMBO J. 2003 Jun 2;22(11):2741-51 PMID: 12773389
  53. Hedgehog signalling in cancer formation and maintenance.
    Nat Rev Cancer. 2003 Dec;3(12):903-11 PMID: 14737121
  54. Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo.
    Nat Neurosci. 2003 Jan;6(1):21-7 PMID: 12469128
  55. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches.
    Neuron. 2003 Sep 11;39(6):937-50 PMID: 12971894
  56. Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened.
    Genes Dev. 2002 Nov 1;16(21):2743-8 PMID: 12414725
  57. Loss-of-function mutations in the human GLI2 gene are associated with pituitary anomalies and holoprosencephaly-like features.
    Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13424-9 PMID: 14581620
  58. GLI gene expression in bone and soft tissue sarcomas of adult patients correlates with tumor grade.
    Cancer Res. 1999 Apr 15;59(8):1890-5 PMID: 10213497
  59. Induction of medulloblastomas in mice by sonic hedgehog, independent of Gli1.
    Cancer Res. 2002 Nov 15;62(22):6385-9 PMID: 12438220
  60. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1.
    Neuron. 1997 Jul;19(1):15-26 PMID: 9247260
  61. Hedgehog-GLI signaling regulates the behavior of cells with stem cell properties in the developing neocortex.
    Development. 2004 Jan;131(2):337-45 PMID: 14681189
  62. Mutations in SUFU predispose to medulloblastoma.
    Nat Genet. 2002 Jul;31(3):306-10 PMID: 12068298
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0404956101
Published
2004-08-24
Epub
2004-00-16
Pages
12561-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC514658
Subset
IM
Grants
NINDS NIH HHS · R01 NS037352-08 · United States
External Links
PubMed source DOI: 10.1073/pnas.0404956101 PMC Full Text View journal details
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