Chen Mengqian, Tanner Matthew, Levine Alice C, Levina Elina, Ohouo Patrice, Buttyan Ralph
Cancer Center, The Ordway Research Institute, 150 New Scotland Avenue, Albany, NY 12208, USA.
Cell Cycle. 2009 Jan 1;8(1):149-57. doi: 10.4161/cc.8.1.7532.
Hedgehog signaling is thought to play a role in several human cancers including prostate cancer. Although prostate cancer cells express many of the gene products involved in hedgehog signaling, these cells are refractory to the canonical signaling effects of exogenous hedgehog ligands or to activated Smoothened, the hedgehog-regulated mediator of Gli transcriptional activation. Here, we show that the expression of hedgehog ligands and some hedgehog target genes are regulated by androgen in the human prostate cancer cell line, LNCaP and its more metastatic variants (C4-2 and C4-2B). Androgen (R1881) strongly suppressed the expression of hedgehog ligands in these cells and their prolonged maintenance in androgen-deficient medium upregulated Sonic and Indian hedgehog mRNA and protein levels by up to 30,000-fold. Hedgehogs were released into the conditioned medium of androgen-deprived LNCaP cells and this medium was able to increase hedgehog target gene expression in hedgehog-responsive mouse fibroblasts (MC3T3-E1). Moreover, this activity was accompanied by increased expression of Gli target genes, Patched 1 and Gli2, in LNCaP that could be suppressed by cyclopamine, indicating that chronic androgen-deprivation also re-awakens the autocrine responsiveness of the cancer cells to hedgehog. In contrast to the suppressive effects of R1881 on hedgehog ligand and Gli2 expression, we found that Gli1 expression in LNCaP cells was induced by R1881. Given the ability of androgen to modulate the expression and release of hedgehog ligands and the activity of the autocrine hedgehog signaling pathway in these prostate cancer cells, our results imply that chronic androgen deprivation therapy (ADT) for prostate cancer might create a hedgehog signaling environment in the region of the tumor that could ultimately impact on the long term effectiveness of this treatment. This consideration supports the idea of clinically testing hedgehog-blocking drugs in conjunction with ADT in patients with advanced prostate cancer.
刺猬信号通路被认为在包括前列腺癌在内的多种人类癌症中发挥作用。尽管前列腺癌细胞表达许多参与刺猬信号通路的基因产物，但这些细胞对外源刺猬配体的经典信号效应或对受刺猬调节的Gli转录激活介质——活化的平滑受体（Smoothened）具有抗性。在此，我们表明，在人前列腺癌细胞系LNCaP及其转移性更强的变体（C4-2和C4-2B）中，刺猬配体和一些刺猬靶基因的表达受雄激素调控。雄激素（R1881）强烈抑制这些细胞中刺猬配体的表达，而在雄激素缺乏的培养基中长时间培养则使音猬因子（Sonic）和印度刺猬因子（Indian hedgehog）的mRNA和蛋白水平上调多达30000倍。刺猬因子被释放到雄激素剥夺的LNCaP细胞的条件培养基中，这种培养基能够增加刺猬反应性小鼠成纤维细胞（MC3T3-E1）中刺猬靶基因的表达。此外，这种活性伴随着LNCaP中Gli靶基因Patched 1和Gli2表达的增加，而环杷明可以抑制这种增加，这表明长期雄激素剥夺也会重新唤醒癌细胞对刺猬因子的自分泌反应性。与R1881对刺猬配体和Gli2表达的抑制作用相反，我们发现R1881可诱导LNCaP细胞中Gli1的表达。鉴于雄激素能够调节这些前列腺癌细胞中刺猬配体的表达和释放以及自分泌刺猬信号通路的活性，我们的结果表明，前列腺癌的长期雄激素剥夺疗法（ADT）可能会在肿瘤区域创造一种刺猬信号环境，这最终可能会影响这种治疗的长期效果。这一考虑支持了在晚期前列腺癌患者中将刺猬信号阻断药物与ADT联合进行临床试验的想法。
