Iida N, Sugiyama A, Myoubudani H, Inoue K, Sugamata M, Ihara T, Ueno Y, Tashiro F
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Science University of Tokyo, Noda, Chiba, Japan.
Carcinogenesis. 1998 Jul;19(7):1191-202. doi: 10.1093/carcin/19.7.1191.
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.
