Suppression of arachidonic acid cascade-mediated apoptosis in aflatoxin B1-induced rat hepatoma cells by glucocorticoids.
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.
Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Science University of Tokyo, Noda, Chiba, Japan.
N
N
Iida
A
A
Sugiyama
H
H
Myoubudani
K
K
Inoue
M
M
Sugamata
T
T
Ihara
Y
Y
Ueno
F
F
Tashiro
D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism / Q000502:physiology*; D002273:Carcinogens / Q000633:toxicity*; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008084:Lipoxygenase / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology
D002273:Carcinogens; D004965:Estrogen Antagonists; D005938:Glucocorticoids; D011453:Prostaglandins; D016212:Transforming Growth Factor beta; D013629:Tamoxifen; D016718:Arachidonic Acid; D004958:Estradiol; D016604:Aflatoxin B1; D008084:Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases