p28GANK knockdown-derived reactive oxygen species induces apoptosis through mitochondrial dysfunction mediated by p38 in HepG2 cells.
Oncoprotein p28GANK knockdown by RNA interference (RNAi) can induce hepatoma cells apoptosis. However, the mechanisms have not been well defined yet. In the present study the p28GANK knockdown-induced apoptosis in HepG2 cells was prevented by caspase-9 inhibitor (Z-LEHD-FMK). During the knockdown of p28GANK, mitochondrial translocation of Bax, loss of mitochondrial transmembrane potential (DeltaPsim) and release of cytochrome c were observed. In this study, the activation of p38 was found to be critical for the p28GANK knockdown-induced apoptosis, as suggested by the finding that pharmacological inhibition of p38 with SB203580 suppressed the redistribution of Bax, the loss of DeltaPsim and the apoptosis. Moreover, generation of reactive oxygen species (ROS) contributed to the cell death because N-acetyl-L-cystenine (NAC), a ROS scavenger, suppressed the phosphorylation of p38 and the apoptosis. Our studies established the signaling pathway of p28GANK knockdown-induced apoptosis in HepG2 cells, namely, mitochondrial dysfunction mediated by p38 downstream of intracellular ROS generation.
Wang
Xuefeng
X
International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Shanghai 200438, P.R.China.
Li
Honghai
H
Chen
Yao
Y
Fu
Jing
J
Ren
Yibin
Y
Dong
Liwei
L
Tang
Shanhua
S
Liu
Shuqin
S
Wu
Mengchao
M
Wang
Hongyang
H
D000111:Acetylcysteine / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D017382:Reactive Oxygen Species; D013347:Subcellular Fractions / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D048051:p38 Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine