Oxidative stress induces p53-dependent apoptosis in hepatoblastoma cell through its nuclear translocation.
Hepatoblastoma (HBL) is the most common malignant liver tumor in children. Since tumor suppressor p53 is rarely mutated in HBL, it remains unknown whether p53 could contribute to the hepatocarcinogenesis. In the present study, we have found for the first time that, like neuroblastoma (NBL), wild-type p53 was abnormally accumulated in the cytoplasm of the human HBL-derived Huh6 cells. In accordance with this notion, immunohistochemical analysis demonstrated that p53 is largely expressed in cytoplasm of human primary HBLs. In response to the oxidative stress, Huh6 cells underwent apoptotic cell death in association with the nuclear translocation of p53 and the transactivation of its target gene implicated in apoptotic cell death. siRNA-mediated knockdown of the endogenous p53 conferred the resistance of Huh6 cells to oxidative stress. Intriguingly, histone deacetylase inhibitor (nicotinamide) treatment strongly inhibited the oxidative stress-induced nuclear translocation of p53 as well as the p53-dependent apoptosis in Huh6 cells. In contrast to the previous observations, the cytoplasmic anchor protein for p53 termed Parc had undetectable effect on the cytoplasmic retention of p53. Collectively, our present results suggest that the abnormal cytoplasmic localization of p53 might contribute at least in part to the development of HBL.
Yamamoto
Hideki
H
Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Ozaki
Toshinori
T
Nakanishi
Mitsuru
M
Kikuchi
Hironobu
H
Yoshida
Kaori
K
Horie
Hiroshi
H
Kuwano
Hiroyuki
H
Nakagawara
Akira
A
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002648:Child; D003593:Cytoplasm / Q000378:metabolism; D018197:Hepatoblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D009536:Niacinamide / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014166:Transferases; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014803:Vitamin B Complex / Q000378:metabolism
D002352:Carrier Proteins; D016877:Oxidants; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014803:Vitamin B Complex; D009536:Niacinamide; D006861:Hydrogen Peroxide; C400192:Cul9 protein, human; D014166:Transferases