In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.
In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.
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DOI：
10.18632/oncotarget.7062
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发表时间：
2016-02-23
期刊：
影响因子：
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通讯作者：
Bei R
中科院分区：
文献类型：
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作者：
Benvenuto M;Masuelli L;De Smaele E;Fantini M;Mattera R;Cucchi D;Bonanno E;Di Stefano E;Frajese GV;Orlandi A;Screpanti I;Gulino A;Modesti A;Bei R
异常的 Hedgehog (Hh)/神经胶质瘤相关癌基因 (GLI) 信号传导与癌症进展有关。在这里，我们使用免疫组织化学分析了 51 例乳腺癌（导管癌）组织中的 GLI1、Sonic Hedgehog (Shh) 和 NF-κB 表达。我们发现导管癌病例中核 GLI1 表达与肿瘤分级呈正相关。细胞质 Shh 染色与较低的肿瘤分级显着相关。接下来，使用 Smoothened (SMO) 拮抗剂 GDC-0449 和直接 GLI1 抑制剂 GANT-61 评估了两种 Hh 信号通路抑制剂对乳腺癌细胞系的体外作用。 GDC-0449和GANT-61表现出以下作用：a)抑制乳腺癌细胞存活； b) 诱导细胞凋亡； c)通过降低GLI1和Ptch的mRNA表达水平并抑制GLI1的核转位来抑制Hh通路活性； d)增加/减少EGFR和ErbB2蛋白表达，降低p21-Ras和ERK1/ERK2 MAPK活性并抑制AKT激活； e) 减少 NF-κB 的核转位。然而，GANT-61 比 GDC-0449 更有效地发挥这些作用。在皮下接种小鼠乳腺癌 (TUBO) 细胞的 BALB/c 小鼠中分析了 GDC-0449 和 GANT-61 的体内抗肿瘤活性。 GDC-0449和GANT-61不同程度地抑制BALB/c小鼠TUBO细胞的肿瘤生长。这些发现表明，使用作用于 SMO 下游的拮抗剂靶向 Hh 通路是一种比使用作用于 SMO 上游的拮抗剂更有效的策略来中断乳腺癌中的 Hh 信号传导。
Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21-Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT-61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer.