Carcinogenesis, Vol 19, 1191-1202, Copyright © 1998 by Oxford University Press
N Iida, A Sugiyama, H Myoubudani, K Inoue, M Sugamata, T Ihara, Y Ueno and F Tashiro
It has been shown that hypophysectomy protects aflatoxin B1 (AFB1)
hepatocarcinogenesis and the prevention of apoptosis is a critical process
for tumorigenesis. In this paper, we analyzed the cell death of
AFB1-induced rat hepatoma Kagura-2 (K2) cells elicited by an estrogen
antagonist, tamoxifen (TAM), and transforming growth factor-beta1 (TGF-
beta1) to elucidate the function of endocrine factors in AFB1
hepatocarcinogenesis. TAM and TGF-beta1 induced a typical apoptosis in K2
cells. The apoptotic cell death was efficiently suppressed by
glucocorticoids (GCs), but not by other steroid compounds including
17beta-estradiol (E2). Cyclo-oxygenase (COX) inhibitors such as aspirin
(ASP) and indomethacin (IND) also inhibited the apoptosis, while inhibitory
effects of general lipoxygenase (LOX) inhibitors such as
nordihydroguaiaretic acid (NDGA) and 5,8,11-eicosatrienoic acid (ETI) were
not observed. TAM and TGF-beta1 enhanced the release of [3H]arachidonic
acid (AA) from pre-labeled K2 cells, which was inhibited by dexamethasone
(DEX). Furthermore, cytosolic phospholipase A2 (cPLA2) activity in K2 cells
treated with TAM for 2 h was higher than that in the control. Prostaglandin
J2 (PGJ2) and delta12-PGJ2, AA metabolites formed in the COX pathway,
induced K2 cell death. These results suggest that AA metabolites are
involved in apoptotic K2 cell death elicited by TAM and TGF-beta1, and GCs
could act as a tumor promoter in AFB1 hepatocarcinogenesis through the
prevention of apoptosis induced by AA metabolites formed in vivo.
ARTICLES
Suppression of arachidonic acid cascade-mediated apoptosis in aflatoxin B1-induced rat hepatoma cells by glucocorticoids
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Science University of Tokyo, Noda, Chiba, Japan.
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