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Convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer.
Phytomedicine ( IF 6.7 ) Pub Date : 2020-01-17 , DOI: 10.1016/j.phymed.2020.153172
Zhi Hong Zhang 1 , Ming Yue Li 1 , Zhe Wang 1 , Hong Xiang Zuo 1 , Jing Ying Wang 1 , Yue Xing 1 , Chenghua Jin 1 , Guanghua Xu 1 , Lianxun Piao 1 , Hongxin Piao 2 , Juan Ma 1 , Xuejun Jin 1
Affiliation  

BACKGROUND Aberrant activation of STAT3 is frequently encountered and promotes survival, cellular proliferation, migration, invasion and angiogenesis in tumor cell. Convallatoxin, triterpenoid ingredient, exhibits anticancer pharmacological properties. PURPOSE In this work, we investigated the anticancer potential of convallatoxin and explored whether convallatoxin mediates its effect through interference with the STAT3 activation in colorectal cancer cells. METHODS In vitro, the underlying mechanisms of convallatoxin at inhibiting STAT3 activation were investigated by homology modeling and molecular docking, luciferase reporter assay, MTT assay, RT-PCR, Western blotting and immunofluorescence assays. Changes in cellular proliferation, apoptosis, migration, invasion and angiogenesis were analyzed by EdU labeling assay, colony formation assay, flow cytometry assay, wound-healing assay, matrigel transwell invasion assay and tube formation assays. And in vivo, antitumor activity of convallatoxin was assessed in a murine xenograft model of HCT116 cells. RESULTS Convallatoxin decreased the viability of colorectal cancer lines. Moreover, convallatoxin reduced the P-STAT3 (T705) via the JAK1, JAK2, and Src pathways and inhibited serine-727 phosphorylation of STAT3 via the PI3K-AKT-mTOR-STAT3 pathways in colorectal cancer cells. Interestingly, we discovered the crosstalk between mTOR and JAK2 in mTOR/STAT3 and JAK/STAT3 pathways, which collaboratively regulated STAT3 activation and convallatoxin play a role in it. Convallatoxin also downregulated the expression of target genes involved cell survival (e.g., Survivin, Bcl-xl, Bcl-2), proliferation (e.g., Cyclin D1), metastasis (e.g., MMP-9), and angiogenesis (e.g., VEGF). Indeed, we found that convallatoxin inhibited tube formation, migration, and invasion of endothelial cells, and inhibited the proliferation. Finally, in vivo observations were confirmed by showing antitumor activity of convallatoxin in a murine xenograft model. CONCLUSION The result of the current study show that convallatoxin promotes apoptosis and inhibits proliferation and angiogenesis through crosstalk between JAK2/STAT3 (T705) and mTOR/STAT3 (S727) signaling pathways in colorectal cancer cells and indicate that convallatoxin could be a valuable candidate for the development of colorectal cancer therapeutic.

中文翻译:

Convallatoxin通过结直肠癌中JAK2 / STAT3(T705)和mTOR / STAT3(S727)信号通路之间的串扰促进凋亡并抑制增殖和血管生成。

背景技术STAT3的异常激活经常被遇到并且促进肿瘤细胞中的存活,细胞增殖,迁移,侵袭和血管生成。三萜类成分Convallatoxin具有抗癌药理作用。目的在这项工作中,我们研究了铃兰辛的抗癌潜力,并探讨了铃兰辛是否通过干扰大肠癌细胞中STAT3的活化来介导其作用。方法在体外,通过同源性建模和分子对接,萤光素酶报道分子测定,MTT测定,RT-PCR,Western印迹和免疫荧光测定,研究了缬沙星抑制STAT3活化的潜在机制。通过EdU标记分析,集落形成分析,细胞增殖,凋亡,迁移,侵袭和血管生成的变化进行了分析,流式细胞仪分析,伤口愈合分析,基质胶穿透孔侵袭分析和管形成分析。并且在体内,在HCT116细胞的小鼠异种移植模型中评估了缬沙星的抗肿瘤活性。结果甲壳素降低了结直肠癌细胞的活力。此外,在大肠癌细胞中,缬草毒素通过JAK1,JAK2和Src途径还原P-STAT3(T705),并通过PI3K-AKT-mTOR-STAT3途径抑制STAT3的丝氨酸727磷酸化。有趣的是,我们在mTOR / STAT3和JAK / STAT3通路中发现了mTOR和JAK2之间的串扰,它们共同调节STAT3的激活,而缬草毒素在其中起作用。Convallatoxin还下调了涉及细胞存活(例如Survivin,Bcl-xl,Bcl-2),增殖(例如Cyclin D1),转移(例如MMP-9)的靶基因的表达,和血管生成(例如,VEGF)。确实,我们发现了缬沙星抑制内皮细胞的管形成,迁移和侵袭,并抑制了增殖。最后,通过在鼠异种移植模型中显示铃兰辛的抗肿瘤活性来证实体内观察。结论目前的研究结果表明,通过在结肠直肠癌细胞中的JAK2 / STAT3(T705)和mTOR / STAT3(S727)信号传导通路之间的串扰,铃兰辛可以促进细胞凋亡并抑制增殖和血管生成,并表明铃兰辛可能是结直肠癌的有价值的候选药物。开发结直肠癌治疗剂。通过在鼠异种移植模型中显示铃兰辛的抗肿瘤活性,证实了体内观察。结论目前的研究结果表明,通过在结肠直肠癌细胞中的JAK2 / STAT3(T705)和mTOR / STAT3(S727)信号传导通路之间的串扰,铃兰辛可以促进细胞凋亡并抑制增殖和血管生成,并表明铃兰辛可能是结直肠癌的有价值的候选药物。开发结直肠癌治疗剂。通过在鼠异种移植模型中显示铃兰辛的抗肿瘤活性,证实了体内观察。结论目前的研究结果表明,通过在结肠直肠癌细胞中的JAK2 / STAT3(T705)和mTOR / STAT3(S727)信号传导通路之间的串扰,铃兰辛可以促进细胞凋亡并抑制增殖和血管生成,并表明铃兰辛可能是结直肠癌的有价值的候选药物。开发结直肠癌治疗剂。
更新日期:2020-01-17
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