SIRT2 mediated antitumor effects of shikonin on metastatic colorectal cancer
SIRT2 mediated antitumor effects of shikonin on metastatic colorectal cancer
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DOI：
10.1016/j.ejphar.2017.01.008
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发表时间：
2017-02-15
影响因子：
5
通讯作者：
Yuan, Qiong
中科院分区：
文献类型：
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作者：
Zhang, Li-Li;Zhan, Lin;Yuan, Qiong
SIRT2参与多种癌症的发展。紫草素是一种已知具有抗肿瘤作用的天然化合物。本研究旨在通过调控SIRT2表达来评估紫草素对结直肠癌（CRC）发生和转移进展的影响，以及这种影响是否与细胞外信号调节激酶（ERKs）的磷酸化有关。结果表明，与邻近的非癌组织（ANCT, n=26）相比，CRC活检样本（n=31）中的SIRT2表达下调。此外，尽管SIRT2在原发肿瘤中缺乏表达，但CRC转移灶中SIRT2呈阳性。此外，体外实验数据显示，SIRT2过表达抑制SW480细胞的增殖和转移进展，而阻断SIRT2表达则诱导HT29细胞的增殖和转移进展。紫草素可抑制SW480细胞的活力、迁移和侵袭，抑制裸鼠肿瘤的生长；而AGK2 （SIRT2的特异性抑制剂）逆转了这些作用。表皮生长因子（EGF， ERK的激活因子）和ERK过表达抑制了紫草素对SW480细胞SIRT2表达、增殖和转移的影响。然而，EGF的这种增殖作用被SIRT2过表达逆转。总之，这些结果提示SIRT2是治疗结直肠癌的一个新的治疗靶点。紫草素对结直肠癌的抗肿瘤作用似乎是通过磷酸化erk抑制SIRT2上调介导的。
SIRT2 is involved in the development of a variety of cancers. Shikonin is a natural compound that is known to have antitumor effects. This study aims to assess the effects of shikonin on the development and metastatic progression of colorectal cancer (CRC) through regulation of SIRT2 expression and whether this effect is related to the phosphorylation of extracellular signal-regulated kinases (ERKs). The results demonstrated that SIRT2 is downregulated in CRC biopsy samples (n=31) compared with the adjacent non-cancerous tissues (ANCT, n=26). Furthermore, CRC metastases were positive for SIRT2 despite a lack of expression in the primary tumor. In addition, data from an in vitro assay revealed that overexpression of SIRT2 inhibited the proliferation and metastatic progression of SW480 cells while blocking of SIRT2 expression induced the proliferation and metastatic progression of HT29 cells. Shikonin inhibited the viability, migration and invasion of SW480 cells and it also inhibited the tumor growth in the nude mice model; while AGK2 (a specific inhibitor of SIRT2) reversed these effects. Epidermal growth factor (EGF, an activator of ERK) and ERK-overexpression inhibited the effects of shikonin on SIRT2 expression, proliferation and metastasis in SW480 cells. However, this proliferative effect of EGF was reversed by SIRT2 overexpression. In conclusion, these results suggest that SIRT2 is a new therapeutic target for the treatment of CRC. The antitumor effects of shikonin on CRC seem to be mediated by SIRT2 upregulation via phospho-ERK inhibition.