title: SIRT2 mediated antitumor effects of shikonin on metastatic colorectal cancer.
abstract: 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.
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhan
authors.affiliation: Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
authors.forename: Yong-Dong
authors.initials: YD
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Zhen-Li
authors.initials: ZL
authors.lastname: Min
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Can
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Immunology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Ya-Jun
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Qing-Ming
authors.initials: QM
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China.
authors.forename: Xia-Min
authors.initials: XM
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Medical College, Wuhan University of Science and Technology, Wuhan 430065, China. Electronic address: yuanqiong@wust.edu.cn.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yuan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009285:Naphthoquinones / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D056565:Sirtuin 2 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; C016101:shikonin; D048049:Extracellular Signal-Regulated MAP Kinases; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: Colorectal cancer; Metastasis; Phospho-extracellular signal-regulated kinases (p-ERK); SIRT2; Shikonin