GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft.
GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft.
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DOI：
10.1016/j.canlet.2012.11.018
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发表时间：
2013-03-01
期刊：
影响因子：
9.7
通讯作者：
Shankar, Sharmila
中科院分区：
文献类型：
--
作者：
Fu, Junsheng;Rodova, Mariana;Roy, Sanjit K.;Sharma, Jay;Singh, Karan P.;Srivastava, Rakesh K.;Shankar, Sharmila
多条证据表明，Sonic Hedgehog（Shh）信号通路在胰腺癌干细胞（CSC）中异常重新激活。本研究的目的是研究GANT-61（Gli转录因子抑制剂）调节干细胞特性和肿瘤生长的分子机制。测量GANT-61对CSC的活力、球体形成、凋亡、DNA结合和转录活性以及上皮-间充质转化（EMT）的影响。使用人源化NOD/SCID/IL 2 R γ小鼠来检查GANT-61对CSC的肿瘤生长的影响。GANT-61抑制细胞活力、球状体形成、Gli-DNA结合和转录活性，并通过激活caspase-3和切割聚ADP核糖聚合酶（PARP）诱导凋亡。GANT-61可增加TRAIL-R1/DR 4、TRAIL-R2/DR 5和Fas的表达，降低PDGFRα和Bcl-2的表达。GANT-61还通过上调E-cadherin和抑制N-cadherin以及转录因子Snail、Slug和Zeb 1来抑制EMT。此外，GANT-61抑制多能性维持因子Nanog、Oct 4、Sox-2和cMyc。通过shRNA抑制Gli 1和Gli 2模拟了在GANT-61处理的胰腺CSC中观察到的细胞活力、球状体形成、凋亡和基因表达的变化。GANT-61还可抑制NOD/SCID IL 2 R γ敲除小鼠肿瘤组织中的肿瘤生长，这与上调DR 4和DR 5表达，抑制Gli 1、Gli 2、Bcl-2、CCND 2和Zeb 1表达有关。我们的数据突出了Shh通路对于胰腺CSC的自我更新和转移的重要性，并且还建议Gli作为胰腺癌消除CSC的治疗靶点。
Multiple lines of evidence suggest that the Sonic Hedgehog (Shh) signaling pathway is aberrantly reactivated in pancreatic cancer stem cells (CSCs). The objectives of this study were to examine the molecular mechanisms by which GANT-61 (Gli transcription factor inhibitor) regulates stem cell characteristics and tumor growth. Effects of GANT-61 on CSC’s viability, spheroid formation, apoptosis, DNA-binding and transcriptional activities, and epithelial-mesenchymal transition (EMT) were measured. Humanized NOD/SCID/IL2Rgammanull mice were used to examine the effects of GANT-61 on CSC’s tumor growth. GANT-61 inhibited cell viability, spheroid formation, and Gli-DNA binding and transcriptional activities, and induced apoptosis by activation of caspase-3 and cleavage of Poly-ADP ribose Polymerase (PARP). GANT-61 increased the expression of TRAIL-R1/DR4, TRAIL-R2/DR5 and Fas, and decreased expression of PDGFRα and Bcl-2. GANT-61 also suppressed EMT by up-regulating E-cadherin and inhibiting N-cadherin and transcription factors Snail, Slug and Zeb1. In addition, GANT-61 inhibited pluripotency maintaining factors Nanog, Oct4, Sox-2 and cMyc. Suppression of both Gli1 plus Gli2 by shRNA mimicked the changes in cell viability, spheroid formation, apoptosis and gene expression observed in GANT-61-treated pancreatic CSCs. Furthermore, GANT-61 inhibited CSC tumor growth which was associated with up-regulation of DR4 and DR5 expression, and suppression of Gli1, Gli2, Bcl-2, CCND2 and Zeb1 expression in tumor tissues derived from NOD/SCID IL2Rγ null mice. Our data highlight the importance of Shh pathway for self-renewal and metastasis of pancreatic CSCs, and also suggest Gli as a therapeutic target for pancreatic cancer in eliminating CSCs.
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