TY - JOUR
T1 - Parkin facilitates proteasome inhibitor-induced apoptosis via suppression of NF-κB activity in hepatocellular carcinoma
AU - Zhang, Xiaolan
AU - Lin, Chun
AU - Song, Junwei
AU - Chen, Han
AU - Chen, Xuhong
AU - Ren, Liangliang
AU - Zhou, Zhongqiu
AU - Pan, Jinyuan
AU - Yang, Zhenjun
AU - Bao, Wenhao
AU - Ke, Xueping
AU - Yang, Jianan
AU - Liang, Yingying
AU - Huang, Hongbiao
AU - Tang, Daolin
AU - Jiang, Lili
AU - Liu, Jinbao
N1 - Funding Information:
This work was supported by the Natural Science Foundation of China (grant numbers 81773213, 81672874, and 81502194), the Science and Technology Program of Guangzhou (201604020001), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS), the Distinguished Young Scholar of Guangdong Province (grant number 2015A030306033), the Natural Science Foundation of Guangdong Province (grant number 2015A030313468), the Young Scholar of Science and Technology of Guangdong Province (grant number 2016TQ03R801), the Innovative Academic Team of Guangzhou Education System (grant number 1201610014), the Natural Science Foundation research team of Guangdong Province (grant number 2018B030312001), the Research Team of the Department of Education of Guangdong Province (grant number 2017KCXTD027), the Guangzhou key medical discipline construction project fund, Guangdong traditional Chinese medicine bureau project (grant number 20161178), and Guangzhou traditional Chinese medicine and traditional Chinese and western medicine science and technology project (grant numbers 2016A011020, 20182A011025).
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072693885&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072693885&partnerID=8YFLogxK
U2 - 10.1038/s41419-019-1881-x
DO - 10.1038/s41419-019-1881-x
M3 - Article
C2 - 31558697
AN - SCOPUS:85072693885
VL - 10
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 10
M1 - 719
ER -