Zhang Jingxian, Lipinski Robert, Shaw Aubie, Gipp Jerry, Bushman Wade
Department of Surgery and McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin 53792, USA.
J Urol. 2007 Mar;177(3):1179-85. doi: 10.1016/j.juro.2006.10.032.
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.
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).
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.
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.
最近的几份报告强调了刺猬信号通路在前列腺癌中的作用。然而，自分泌和旁分泌刺猬信号通路对肿瘤生长和进展的相对贡献尚不清楚。由于在已建立的人前列腺癌细胞系中关于自分泌信号通路存在与否的报告相互矛盾，用于药物开发的自分泌信号通路建模工作受到了阻碍。
我们全面表征了3种前列腺癌细胞系LNCaP、PC3和22RV1（美国典型培养物保藏中心，弗吉尼亚州马纳萨斯）中刺猬信号通路基因的表达。我们还检测了它们对Shh配体和刺猬信号通路抑制剂环杷明（多伦多研究化学品公司，加拿大安大略省多伦多）的反应。
所有3种细胞系中刺猬配体、patched和Gli1的表达均低于正常人前列腺组织中的表达水平。当用激活形式的Gli2转染时，所有3种细胞系均显示刺猬靶基因激活，但没有一种细胞系对刺猬配体或用激活形式的 smoothened转染表现出可检测到的转录反应。此外，尽管环杷明抑制培养中的细胞增殖，但用刺猬信号通路抑制剂环杷明处理并未抑制3种前列腺癌细胞系中任何一种的刺猬靶基因表达。
LNCaP、PC3和22RV1没有显示出通过配体依赖性机制进行自分泌信号传导的证据，并且环杷明介导的培养中生长抑制的发生对经典刺猬信号通路活性没有任何可辨别的影响。
