WP1130 increases doxorubicin sensitivity in hepatocellular carcinoma cells through usp9x-dependent p53 degradation.
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.
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Hao
H
Liu
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Wei
W
Chen
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Chao
C
Liang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Bryan Wei
BW
Chen
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xiao
X
Zhi
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Shufeng
S
Zhang
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xiaoxiao
X
Zheng
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Xueli
X
Bai
Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Electronic address: liangtingbo@zju.edu.cn.
Tingbo
T
Liang
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003487:Cyanoacrylates; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*
D003487:Cyanoacrylates; D009570:Nitriles; D011725:Pyridines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C506234:USP9X protein, human; C519751:degrasyn; D004317:Doxorubicin; D043222:Ubiquitin Thiolesterase
Drug resistance; Hepatocellular carcinoma; WP1130; p53; usp9x