Lack of demonstrable autocrine hedgehog signaling in human prostate cancer cell lines.
OBJECTIVE
Several recent reports highlighted the role of hedgehog signaling in prostate cancer. However, the relative contributions of autocrine and paracrine hedgehog signaling to tumor growth and progression are unclear. Efforts to model autocrine signaling for drug development have been hampered by conflicting reports of the presence or absence of autocrine signaling in established human prostate cancer cell lines.


METHODS
We comprehensively characterized the expression of hedgehog pathway genes in the 3 prostate cancer cell lines LNCaP, PC3 and 22RV1 (American Type Culture Collection, Manassas, Virginia). We also examined their response to Shh ligand and to the hedgehog pathway inhibitor cyclopamine (Toronto Research Chemicals, Toronto, Ontario, Canada).


RESULTS
Expression of hedgehog ligand, patched and Gli1 in all 3 cell lines was lower than the expression level in normal human prostate tissue. All 3 cell lines showed hedgehog target gene activation when transfected with an activated form of Gli2 but none showed a detectable transcriptional response to hedgehog ligand or to transfection with an activated form of smoothened. Furthermore, treatment with the hedgehog pathway inhibitor cyclopamine did not inhibit hedgehog target gene expression in any of the 3 prostate cancer cell lines, although cyclopamine inhibited proliferation in culture.


CONCLUSIONS
LNCaP, PC3 and 22RV1 show no evidence of autocrine signaling by ligand dependent mechanisms and cyclopamine mediated inhibition of growth in culture occurs without of any discernible effect on canonical hedgehog pathway activity.
Zhang
Jingxian
J
Department of Surgery and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53792, USA.
Lipinski
Robert
R
Shaw
Aubie
A
Gipp
Jerry
J
Bushman
Wade
W
D019898:Autocrine Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D000072079:Patched Receptors; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; D053823:Hedgehog Proteins; C509246:IHH protein, human; D000072079:Patched Receptors; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1