WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation

被引：61

作者：

Liu, Hao ^{[1
]}

Chen, Wei ^{[1
]}

Liang, Chao ^{[1
]}

Chen, Bryan Wei ^{[1
]}

Zhi, Xiao ^{[1
]}

Zhang, Shufeng ^{[1
]}

Zheng, Xiaoxiao ^{[1
]}

Bai, Xueli ^{[1
]}

Liang, Tingbo ^{[1
]}

机构：

[1] Zhejiang Univ, Sch Med, Affiliated Hosp 2, Dept Hepatobiliary & Pancreat Surg, Hangzhou 310003, Zhejiang, Peoples R China

来源：

CANCER LETTERS | 2015年 / 361卷 / 01期

基金：

中国国家自然科学基金; 国家杰出青年科学基金;

关键词：

Hepatocellular carcinoma; Drug resistance; WP1130; usp9x; p53; DRUG-RESISTANCE; CANCER CELLS; DEUBIQUITINATION; UBIQUITINATION; CHEMOTHERAPY; SUPPRESSION; METASTASIS; STABILIZES;

D O I：

10.1016/j.canlet.2015.03.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma (HCC) therapy. However, the underlying mechanisms are not well understood. Recent evidence suggests that deubiquitinases (DUB) are key regulators in the mechanisms of cell proliferation, apoptosis and chemoresistance. The present study aimed to investigate whether WP1130, which inhibits activity of deubiquitinases, exerts synergistic cytotoxicity with doxorubicin in HCC and the underlying mechanisms. In the study, we found that Huh7, HepG2, and SNU387 HCC cells with p53 expression displayed enhanced response to the combination therapy compared with p53-deficient HCC cells (Hep3B) in the manner of inhibiting cell proliferation. Downregulation of p53 abolished the synergistic cytotoxicity of doxorubicin and WP1130 on HCC cells. Mechanistically, we found that combined treatment with WP1130 suppressed doxorubicin-mediated upregulation of p53 via promoting its ubiquitin-proteasome dependent degradation, whereas knockdown of DUB usp9x abolished this effect. Taken together, these results demonstrate that combined treatment with WP1130 sensitized HCC cells to doxorubicin via usp9x-depedent p53 degradation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.

引用

页码：218 / 225

页数：8

共 32 条

[1] p53 ubiquitination: Mdm2 and beyond [J].