Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-κB activity in hepatocellular carcinoma.

Abstract

The ubiquitin-proteasome system (UPS) is a tight homeostatic control mechanism of intracellular protein degradation and turnover involved in many human diseases. Proteasome inhibitors were initially developed as anticancer agents with potential benefits in the suppression of tumor growth. However, clinical trials of patients with solid tumors fail to demonstrate the same efficacy of these proteasome inhibitors. Here, we show that Parkin, an E3 ubiquitin ligase, is implicated in tumorigenesis and therapy resistance of hepatocellular carcinoma (HCC), the most common type of primary liver cancer in adults. Lower Parkin expression correlates with poor survival in patients with HCC. Ectopic Parkin expression enhances proteasome inhibitor-induced apoptosis and tumor suppression in HCC cells in vitro and in vivo. In contrast, knockdown of Parkin expression promotes apoptosis resistance and tumor growth. Mechanistically, Parkin promotes TNF receptor-associated factor (TRAF) 2 and TRAF6 degradation and thus facilitates nuclear factor-kappa-B (NF-κB) inhibition, which finally results in apoptosis. These findings reveal a direct molecular link between Parkin and protein degradation in the control of the NF-κB pathway and may provide a novel UPS-dependent strategy for the treatment of HCC by induction of apoptosis.

• Authors: Xiaolan Zhang, Chun Lin, Junwei Song, Han Chen, Xuhong Chen, Liangliang Ren, Zhongqiu Zhou, Jinyuan Pan, Zhenjun Yang, Wenhao Bao, Xueping Ke, Jianan Yang, Yingying Liang, Hongbiao Huang, Daolin Tang, Lili Jiang, Jinbao Liu
• Journal: Cell death & disease (Cell Death Dis) Vol. 10 Issue 10 Pg. 719 (09 26 2019) ISSN: 2041-4889 [Electronic] England
• PMID: 31558697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Intracellular Signaling Peptides and Proteins
• NF-kappa B
• PSMD2 protein, human
• Proteasome Inhibitors
• TNF Receptor-Associated Factor 2
• Tifab protein, human
• Ubiquitin
• Ubiquitin-Protein Ligases
• parkin protein
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Carcinoma, Hepatocellular (enzymology, metabolism, mortality, pathology)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Databases, Genetic
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Liver Neoplasms (enzymology, metabolism, mortality, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (antagonists & inhibitors)
• Proteasome Endopeptidase Complex (metabolism)
• Proteasome Inhibitors (pharmacology)
• Signal Transduction (drug effects, genetics)
• TNF Receptor-Associated Factor 2 (metabolism)
• Tissue Array Analysis
• Transplantation, Heterologous
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)