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

Cancer Letters
Hao LiuTing-Bo Liang

Abstract

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.

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Citations

Mar 22, 2016·Hepatic Oncology·Josiah Cox, Steven Weinman
Oct 19, 2017·Cancer Metastasis Reviews·Xin ChenJinbao Liu
Feb 1, 2020·The Kaohsiung Journal of Medical Sciences·Zhen-Lin GuLin-Lin Zhen
Feb 23, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Weiwei ShengJianping Zhou
Jun 19, 2020·Cancers·Ainsley Mike AntaoSuresh Ramakrishna
Mar 27, 2019·Cancer Cell International·Hao LuoYingli Wu
Jan 23, 2020·Journal of Cell Science·Rachel O'Dea, Corrado Santocanale
Jun 15, 2019·The Journal of Cell Biology·Andrew KodaniJeremy F Reiter
Apr 10, 2020·International Journal of Molecular Sciences·Keng Po LaiWilliam Ka Fai Tse
Feb 27, 2018·Frontiers in Cell and Developmental Biology·Ishita GuptaSameena Khan
Aug 27, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Ji ChengWenyi Wei
Jan 4, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xiaoli HuXueqiong Zhu
Jan 21, 2021·International Journal of Molecular Sciences·Qi LiuWei Zhang
May 1, 2021·International Journal of Molecular Sciences·Shiyao ChenHuchen Zhou
Jun 3, 2021·International Journal of Molecular Sciences·Tingting Zou, Zhenghong Lin

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