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

Autor:	Zhang X; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Lin C; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Song J; Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry and Molecular Biology, Health Science Center, Shenzhen University, 518060, Shenzhen, China., Chen H; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Chen X; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Ren L; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, 510080, Guangzhou, China., Zhou Z; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Pan J; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Yang Z; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Bao W; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Ke X; Department of Gastroenterology, the Liwan Hospital of the Third Affiliated Hospital of Guangzhou Medical University, 510175, Guangzhou, China., Yang J; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China.; Department of Urologic Oncosurgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 510095, Guangzhou, China., Liang Y; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China.; Department of Ultrasonography, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, 510623, Guangzhou, China., Huang H; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China., Tang D; Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Jiang L; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China. jianglili@gzhmu.edu.cn., Liu J; Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, 511436, Guangzhou, China. jliu@gzhmu.edu.cn.
Jazyk:	angličtina
Zdroj:	Cell death & disease [Cell Death Dis] 2019 Sep 26; Vol. 10 (10), pp. 719. Date of Electronic Publication: 2019 Sep 26.
DOI:	10.1038/s41419-019-1881-x
Abstrakt:	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.
Databáze:	MEDLINE
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