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Verbascoside promotes apoptosis by regulating HIPK2–p53 signaling in human colorectal cancer

期刊名:BMC Cancer
文献编号:DOI: 10.1186/1471-2407-14-747
文献地址: http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-14-747
发表日期:5 October 2014

Abstract

 

Background

We investigated the role of the HIPK2–p53 signaling pathway in tumorigenesis and resistance to the drug Verbascoside (VB) in colorectal cancer (CRC), using in vivo and in vitro experiments.

 

Methods

Primary human CRC samples and normal intestinal tissues from patients were analyzed for HIPK2 expression by immunohistochemistry (IHC) and its expression was correlated against patients’ clinicopathological characteristics. Human CRC HCT-116 cells were implanted in BALB/c nude mice; mice with xenografted tumors were randomly administrated vehicle (control), 20, 40, or 80 mg/mL VB, or 1 mg/mL fluorouracil (5-FU). HIPK2, p53, Bax, and Bcl-2 expression in these tumors were determined by IHC. In vitro effects of VB on CRC cell proliferation and apoptosis were measured by CCK-8 assay and flow cytometry; HIPK2, p53, p-p53, Bax, and Bcl-2 were measured by western blot.

 

Results

IHC analysis for 100 human CRC tumor samples and 20 normal intestinal tissues, showed HIPK2 expression to inversely correlate with Dukes stage and depth of invasion in CRC (P?<?0.05). In vivo, the inhibition rates of 20, 40, and 80 mg/mL VB on CRC xenograft tumor weight were 42.79%, 53.90%, and 60.99%, respectively, and were accompanied by increased expression of HIPK2, p53, and Bax, and decreased Bcl-2 expression in treated tumors. In vitro, VB significantly inhibited proliferation of CRC cell lines HCT-116, HT-29, LoVo, and SW620, in a time- and dose-dependent manner. The apoptosis rates of 25, 50, and 100 μM VB on HCT-116 cells were 10.83?±?1.28, 11.25?±?1.54, and 20.19?±?2.87%, and on HT-29 cells were 18.92?±?6.12, 21.57?±?4.05, and 25.14?±?6.73%, respectively. In summary, VB treatment significantly enhanced the protein expression of pro-apoptotic HIPK2, p53, p-p53, Bax, and decreased anti-apoptotic Bcl-2 expression in CRC cells.

 

Conclusions

HIPK2 protein modulates the phosphorylation status of p53, and levels of Bax and Bcl-2 in CRC. We also found that VB effectively activated the HIPK2–p53 signaling pathway, resulting in increased CRC cell apoptosis.

 

......culture media was replaced with 200 μL culture medium containing Verbascoside (VB) (purity >98%, purchased from Chendu Herb purify Biotechnology Co., Ltd, Chendu, China, serial number: 20100123)......

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