Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2-STAT1-Mcl-1 axis.
Ruxolitinib induces apoptosis of human colorectal cancer cells by downregulating the JAK1/2-STAT1-Mcl-1 axis.
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DOI：
10.3892/ol.2021.12613
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发表时间：
2021-05
期刊：
影响因子：
2.9
通讯作者：
Liu F
中科院分区：
文献类型：
--
作者：
Li X;Wang Z;Zhang S;Yao Q;Chen W;Liu F
在病理条件下，Janus Kinase(JAK)/STAT信号通路可以调节肿瘤细胞的增殖、分化和迁移，包括结直肠癌(CRC)。结直肠癌是世界上男性第三大癌症，女性第二大癌症。在中国中，结直肠癌是男性和女性中第五常见的癌症。采用免疫印迹、流式细胞术、RNA干扰、免疫沉淀法、异种移植模型和免疫组织化学染色等方法对Ruxolitinib的作用机制进行研究。提示Ruxolitinib可通过诱导细胞凋亡来抑制肿瘤细胞的增殖。首先确定JAK1/2-STAT1为鲁索利替尼的靶点。Ruxolitinib下调髓系白血病细胞白血病-1(Mcl-1)的mRNA水平，降低其蛋白水平，从而使Bak能够触发结直肠癌细胞的凋亡。此外，Ruxolitinib在体内对结直肠癌异种移植瘤生长有很强的抑制作用。在44对结肠癌及癌旁正常组织中也证实了磷酸化STAT1(S727)的高表达。综上所述，Ruxolitinib在体内外均能降低JAK1/2-STAT1-Mcl-1蛋白水平，有效抑制结直肠癌细胞的增殖。因此，Ruxolitinib有望成为治疗结直肠癌的一种有前景的抗癌药物。
Under pathological conditions, the Janus kinase (JAK)/STAT signaling pathway can regulate the proliferation, differentiation and migration of tumor cells, including colorectal cancer (CRC). CRC is the third major types of cancer among males and the second among females worldwide. In China, CRC is the fifth common cancer among both males and females. Western blotting, flow cytometry, RNA interference, immunoprecipitation, xenografts models, and immunohistochemical staining were carried out to evaluate the possible mechanisms of acton of ruxolitinib. The present data suggested that ruxolitinib can suppress CRC cell proliferation by inducing apoptosis. Firstly, JAK1/2-STAT1 was identified as the target of ruxolitinib. Then, ruxolitinib downregulated myeloid cell leukemia-1 (Mcl-1) mRNA level and decreased its protein level, which enabled Bak to trigger CRC apoptosis. Furthermore, ruxolitinib exerted potent activity against CRC xenograft growth in vivo. High expression of phosphorylated STAT1 (S727) was also confirmed in 44 pairs of human colon carcinoma and adjacent normal tissues. Taken together, the results showed that ruxolitinib decreased JAK1/2-STAT1-Mcl-1 protein level and effectively suppressed CRC cell proliferation in vitro and in vivo. Therefore, ruxolitinib could be a promising anticancer agent for CRC treatment.
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影响因子：
16.6
作者：
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