Sanchez Pilar, Hernández Ana Maria, Stecca Barbara, Kahler Andrea J, DeGueme Amy M, Barrett Andrea, Beyna Mercedes, Datta Milton W, Datta Sumana, Ruiz i Altaba Ariel
Skirball Institute and Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12561-6. doi: 10.1073/pnas.0404956101. Epub 2004 Aug 16.
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.
前列腺癌是男性中最常见的实体瘤，它与所有癌症一样，具有细胞增殖升高且非稳态的特征。在此，我们检验了“音猬因子（SHH）-GLI信号通路与前列腺癌有关”这一假说。我们报告了SHH-GLI通路成分在成人前列腺癌中的表达情况，肿瘤中的表达水平通常高于正常前列腺上皮。用环杷明或抗SHH抗体阻断该通路可抑制GLI1+/PSA+原发性前列腺肿瘤培养物的增殖。相反，SHH可增强肿瘤细胞增殖，这表明自分泌信号可能常维持肿瘤生长。此外，用环杷明或通过GLI1 RNA干扰阻断三种转移性前列腺癌细胞系中的该通路，会导致细胞增殖受到抑制，这表明在不同水平存在细胞自主通路激活，并显示GLI1在人类细胞中起关键作用。我们的数据证明了前列腺癌对SHH-GLI功能的依赖性，并提示了一种新的治疗方法。
