SUPPRESSION OF ARACHIDONIC-ACID CASCADE-MEDIATED APOPTOSIS IN AFLATOXIN B-1-INDUCED RAT HEPATOMA-CELLS BY GLUCOCORTICOIDS

It has been shown that hypophysectomy protects aflatoxin B-1 (AFB(1)) hepatocarcinogenesis and the prevention of apoptosis is a critical pro cess for tumorigenesis. In this paper, we analyzed the cell death of A FB(1)-induced rat hepatoma Kagura-2 (K2) cells elicited by an estrogen antagonist, tamoxifen (TAM), and transforming growth factor-beta 1 (T GF-beta 1) to elucidate the function of endocrine factors in AFB(1) he patocarcinogenesis. TAM and TGF-beta 1 induced a typical apoptosis in K2 cells, The apoptotic cell death was efficiently suppressed by gluco corticoids (GCs), but not by other steroid compounds including 17 beta -estradiol (E-2), Cyclo-oxygenase (COX) inhibitors such as aspirin (AS P) and indomethacin (IND) also inhibited the apoptosis, while inhibito ry effects of general lipoxygenase (LOX) inhibitors such as nordihydro guaiaretic acid (NDGA) and 5,8,11-eicosatrienoic acid (ETI) were not o bserved, TAM and TGF-beta 1 enhanced the release of [H-3]arachidonic a cid (AA) from pre-labeled K2 cells, which was inhibited by dexamethaso ne (DEX), Furthermore, cytosolic phospholipase A(2) (cPLA(2)) activity in K2 cells treated with TAM for 2 h was higher than that in the cont rol. Prostaglandin J(2) (PGJ(2)) and Delta(12)-PGJ(2), AA metabolites formed in the COX pathway, induced K2 cell death, These results sugges t that AA metabolites are involved in apoptotic K2 cell death elicited by TAM and TGF-beta(1), and GCs could act as a tumor promoter in AFB( 1) hepatocarcinogenesis through the prevention of apoptosis induced by AA metabolites formed in vivo.