Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation.
Arsenic trioxide prevents osteosarcoma growth by inhibition of GLI transcription via DNA damage accumulation.
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DOI：
10.1371/journal.pone.0069466
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Setoguchi T
中科院分区：
文献类型：
--
作者：
Nakamura S;Nagano S;Nagao H;Ishidou Y;Yokouchi M;Abematsu M;Yamamoto T;Komiya S;Setoguchi T
Hedgehog通路在各种类型的恶性肿瘤中被激活。我们以前报道过抑制SMO或GLI可以在体外和体内阻止骨肉瘤的生长。最近，有报道三氧化二砷（ATO）通过阻断GLI转录抑制肿瘤生长。本研究旨在探讨ATO在骨肉瘤发病机制中的作用。实时荧光定量PCR显示ATO可降低人骨肉瘤细胞系中Hedgehog靶基因PTCH 1、GLI 1和GLI 2的表达。WST-1实验和集落形成实验表明ATO能抑制骨肉瘤的生长。这些发现表明ATO在体外阻止GLI转录和骨肉瘤生长。流式细胞仪分析显示ATO促进凋亡细胞死亡。彗星试验表明ATO处理增加了DNA损伤的积累。Western blot分析显示ATO处理增加了γ H2 AX、裂解的PARP和裂解的caspase-3的表达。此外，ATO处理可降低Bcl-2和Bcl-xL的表达。这些发现表明ATO处理促进了由DNA损伤积累引起的凋亡性细胞死亡。相反，Sonic Hedgehog处理降低顺铂处理诱导的γ H2 AX的表达。ATO再诱导通过Sonic Hedgehog处理减弱的DNA损伤的积累。这些发现表明ATO抑制Hedgehog信号的激活，并通过DNA损伤的积累促进骨肉瘤细胞的凋亡。最后，对小鼠异种移植模型的检查表明，ATO给药可以阻止裸小鼠骨肉瘤的生长。由于ATO是FDA批准的治疗白血病的药物，我们的研究结果表明ATO是治疗骨肉瘤患者的一种新的治疗选择。
The Hedgehog pathway is activated in various types of malignancies. We previously reported that inhibition of SMO or GLI prevents osteosarcoma growth in vitro and in vivo. Recently, it has been reported that arsenic trioxide (ATO) inhibits cancer growth by blocking GLI transcription. In this study, we analyzed the function of ATO in the pathogenesis of osteosarcoma. Real-time PCR showed that ATO decreased the expression of Hedgehog target genes, including PTCH1, GLI1, and GLI2, in human osteosarcoma cell lines. WST-1 assay and colony formation assay revealed that ATO prevented osteosarcoma growth. These findings show that ATO prevents GLI transcription and osteosarcoma growth in vitro. Flow cytometric analysis showed that ATO promoted apoptotic cell death. Comet assay showed that ATO treatment increased accumulation of DNA damage. Western blot analysis showed that ATO treatment increased the expression of γH2AX, cleaved PARP, and cleaved caspase-3. In addition, ATO treatment decreased the expression of Bcl-2 and Bcl-xL. These findings suggest that ATO treatment promoted apoptotic cell death caused by accumulation of DNA damage. In contrast, Sonic Hedgehog treatment decreased the expression of γH2AX induced by cisplatin treatment. ATO re-induced the accumulation of DNA damage attenuated by Sonic Hedgehog treatment. These findings suggest that ATO inhibits the activation of Hedgehog signaling and promotes apoptotic cell death in osteosarcoma cells by accumulation of DNA damage. Finally, examination of mouse xenograft models showed that ATO administration prevented the growth of osteosarcoma in nude mice. Because ATO is an FDA-approved drug for treatment of leukemia, our findings suggest that ATO is a new therapeutic option for treatment of patients with osteosarcoma.
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DOI：
10.1073/pnas.1006822107
发表时间：
2010-07-27
影响因子：
11.1
作者：
Kim, Jynho;Lee, John J.;Beachy, Philip A.
通讯作者：
Beachy, Philip A.
影响因子：
11.2
作者：
Regl, G;Kasper, M;Aberger, F
通讯作者：
Aberger, F
影响因子：
56.9
作者：
Berman, DM;Karhadkar, SS;Beachy, PA
通讯作者：
Beachy, PA
影响因子：
37.3
作者：
Hirotsu M;Setoguchi T;Sasaki H;Matsunoshita Y;Gao H;Nagao H;Kunigou O;Komiya S
通讯作者：
Komiya S
影响因子：
1.7
作者：
Iwamoto, Yukihide;Tanaka, Kazuhiro;Yamawaki, Shinya
通讯作者：
Yamawaki, Shinya