Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3.
Lycorine Displays Potent Antitumor Efficacy in Colon Carcinoma by Targeting STAT3.
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Lycorine 通过靶向 STAT3 在结肠癌中显示出强大的抗肿瘤功效
DOI：
10.3389/fphar.2018.00881
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发表时间：
2018
影响因子：
5.6
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Wu S;Qiu Y;Shao Y;Yin S;Wang R;Pang X;Ma J;Zhang C;Wu B;Koo S;Han L;Zhang Y;Gao X;Wang T;Yu H
信号转导子和转录激活子3（STAT 3）是肿瘤治疗的一个有吸引力的治疗靶点。在这项研究中，我们确定石蒜碱是一种有效的STAT 3抑制剂，导致结肠癌中多种致癌过程的抑制。石蒜碱选择性灭活磷酸化STAT 3（Tyr-705），随后的分子对接发现石蒜碱直接结合STAT 3的SH 2结构域。因此，我们发现石蒜碱在体外对人大肠癌（CRC）具有抗增殖活性并诱导细胞凋亡。石蒜碱诱导半胱天冬酶依赖性线粒体凋亡途径的激活，如通过半胱天冬酶的激活和Bax/Bcl-2的比率和线粒体去极化的增加所指示的。过表达STAT 3极大地阻断了石蒜碱在CRC细胞中的这些作用。最后，石蒜碱通过靶向STAT 3在异种移植结直肠肿瘤中表现出潜在的治疗效果，而没有观察到毒性。总之，本研究表明石蒜碱作为一种有前途的STAT 3抑制剂，可阻断结肠癌的肿瘤发生。
Signal transducer and activator of transcription 3 (STAT3) is an attractive therapeutic target for cancer treatment. In this study, we identify lycorine is an effective inhibitor of STAT3, leading to repression of multiple oncogenic processes in colon carcinoma. Lycorine selectively inactivates phospho-STAT3 (Tyr-705), and subsequent molecular docking uncovers that lycorine directly binds to the SH2 domain of STAT3. Consequently, we find that lycorine exhibits anti-proliferative activity and induces cell apoptosis on human colorectal cancer (CRC) in vitro. Lycorine induces the activation of the caspase-dependent mitochondrial apoptotic pathway, as indicated by activation of caspase and increase of the ratio of Bax/Bcl-2 and mitochondrial depolarization. Overexpressing STAT3 greatly blocks these effects by lycorine in CRC cells. Finally, lycorine exhibits a potential therapeutic effect in xenograft colorectal tumors by targeting STAT3 without observed toxicity. Taken together, the present study indicates that lycorine acts as a promising inhibitor of STAT3, which blocks tumorigenesis in colon carcinoma.