Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β InactivationMediated Repression of the Hedgehog/ Gli1 Pathway
Degalactotigonin, a Natural Compound from Solanum nigrum L., Inhibits Growth and Metastasis of Osteosarcoma through GSK3β InactivationMediated Repression of the Hedgehog/ Gli1 Pathway
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DOI：
10.1158/1078-0432.ccr-17-0692
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发表时间：
2018-01-01
影响因子：
11.5
通讯作者：
Shen, Jingnan
中科院分区：
文献类型：
--
作者：
Zhao, Zhiqiang;Jia, Qiang;Shen, Jingnan
目的：从天然来源中提取的具有抗肿瘤特性的药物由于其安全性、有效性和即时可用性而引起了研究人员和临床医生的极大关注。去半乳糖苷（DGT），从龙葵中提取，具有抗癌特性，无严重副作用。本研究旨在探讨DGT对骨肉瘤细胞生长和转移的抑制作用。实验设计：采用MTT法、集落形成实验和细胞凋亡实验检测DGT对骨肉瘤细胞生长和转移的影响。用Transwell法测定细胞的迁移和侵袭能力。通过动物模型研究DGT在骨肉瘤生长和转移中的作用。Gli 1的表达和功能在骨肉瘤细胞和临床标本中进行了测定。DGT处理后，Gli 1的激活和多种细胞激酶的磷酸化状态进行了测量与荧光素酶报告和磷酸激酶抗体array.Results：DGT抑制骨肉瘤细胞增殖，诱导凋亡，并抑制迁移和侵袭。肿瘤接种后腹腔注射DGT，可显著减少骨肉瘤异种移植物的体积，并显著减少骨肉瘤异种移植物转移到肺部的发生。从机制上讲，DGT通过抑制Hedgehog/Gli 1通路抑制骨肉瘤的生长和转移，Hedgehog/Gli 1通路维持恶性表型并参与骨肉瘤患者的预后。DGT降低了影响骨肉瘤患者生存的多种细胞内激酶的活性，包括GSK 3b。结论：DGT可通过抑制Hedgehog/Gli 1通路的GSK 3b失活而抑制骨肉瘤的生长和转移。(C)2017年AACR。
Purpose: Agents extracted from natural sources with antitumor property have attracted considerable attention from researchers and clinicians because of their safety, efficacy, and immediate availability. Degalactotigonin (DGT), extracted from Solanum nigrum L., has anticancer properties without serious side effects. Here, we explored whether DGT can inhibit the growth and metastasis of osteosarcoma.Experimental Design: MTT, colony formation, and apoptosis assays were performed to analyze the effects of DGT on osteosarcoma cell viability in vitro. The migration and invasion abilities were measured using a Transwell assay. Animal models were used to assess the roles of DGT in both tumor growth and metastasis of osteosarcoma. Gli1 expression and function were measured in osteosarcoma cells and clinical samples. After DGT treatment, Gli1 activation and the phosphorylation status of multiple cellular kinases were measured with a luciferase reporter and phospho-kinase antibody array.Results: DGT inhibited proliferation, induced apoptosis, and suppressed migration and invasion in osteosarcoma cells. DGT, injected intraperitoneally after tumor inoculation, significantly decreased the volume of osteosarcoma xenografts and dramatically diminished the occurrence of osteosarcoma xenograft metastasis to the lungs. Mechanistically, DGT inhibited osteosarcoma growth and metastasis through repression of the Hedgehog/Gli1 pathway, which maintains malignant phenotypes and is involved in the prognosis of osteosarcoma patients. DGT decreased the activity of multiple intracellular kinases that affect the survival of osteosarcoma patients, including GSK3b. In addition, DGT represses the Hedgehog/Gli1 pathway mainly through GSK3b inactivation.Conclusions: Our studies provide evidence that DGT can suppress the growth and metastasis of human osteosarcoma through modulation of GSK3b inactivation-mediated repression of the Hedgehog/Gli1 pathway. (C) 2017 AACR.