Proteasome inhibitor MG132 potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells via DR5-dependent pathway.
TRAIL is a tumor-selective apoptosis-inducing cytokine playing a vital role in the surveillance and elimination of some tumor cells. However, some tumors are resistant to TRAIL treatment. Proteasome inhibitor MG132 exhibits anti-proliferative and pro-apoptotic properties in many tumors. In this study, we demonstrated that proteasome inhibitor MG132 in vitro and in vivo potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells. MG132 was able to inhibit the proliferation of GBC-SD cells and induce apoptosis in a dose-dependent manner. The induction of apoptosis by proteasome inhibitor MG132 was mainly through the extrinsic apoptotic pathways of caspase activation such as caspase-8, caspase-3 and PARP cleavage. In addition, this process was also dependent on the upregulation of death receptor 5 (DR5), which promoted TRAIL-induced apoptosis in GBC-SD cells. Taken together, these findings indicate that MG132 possesses anti-gallbladder cancer potential that correlate with regulation of DR5-dependent pathway, and suggest that MG132 may be a promising agent for sensitizing GBC-SD cells to TRAIL-induced apoptosis.
Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Weiping
W
Zhu
Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Dihua
D
Zhan
Department of Hepatic Surgery, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
Lu
L
Wang
Department of Liver Surgery, The Affiliated Zhongshan Hospital of Fudan University, Shanghai 200032, P.R. China.
Dening
D
Ma
Department of General Surgery, Pudong New Area District Zhoupu Hospital, Shanghai 201318, P.R. China.
Mingrong
M
Cheng
Department of General Surgery, The Affiliated Shanghai Fifth People's Hospital of Fudan University, Shanghai 200240, P.R. China.
Huipeng
H
Wang
Department of General Surgery, The Affiliated Shanghai Fifth People's Hospital of Fudan University, Shanghai 200240, P.R. China.
Jiaying
J
Zhao
Department of General Surgery, The Affiliated Shanghai Fifth People's Hospital of Fudan University, Shanghai 200240, P.R. China.
Yuankun
Y
Cai
Department of General Surgery, The Affiliated Shanghai Fifth People's Hospital of Fudan University, Shanghai 200240, P.R. China.
Zhijian
Z
Cheng
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005704:Gallbladder / Q000187:drug effects; D005706:Gallbladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology*; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D007976:Leupeptins; D061988:Proteasome Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D053148:Caspase 3; D053181:Caspase 8; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde