REGULATION OF SPERMIDINE SPERMINE N-1-ACETYLTRANSFERASE EXPRESSION BYCYTOKINES AND POLYAMINES IN HUMAN HEPATOCARCINOMA CELLS (HEPG2)/

Spermidine/spermine N-1-acetyltransferase (cSAT), a key enzyme in poly amine degradation, is induced by various hepatotoxins and liver tumor promoters. In this paper we demonstrate that physiological factors, su ch as cytokines, control cSAT expression in HepG2 human hepatocarcinom a cells. Hepatocyte growth factor (HGF) induced the cSAT mRNA precurso r (3.5 kb) at 4 h. The mature form of mRNA (1.3 kb) increased 6-8-fold between 8 and 10 h, and remained elevated until 18 h. An increase in cSAT activity (2-fold) and high levels of N-1-acetylspermidine were ob served concomitantly. Interleukin-1 beta (IL-1 beta) enhanced cSAT exp ression (both mRNA and enzyme activity) similar to HGF, while tumor ne crosis factor-alpha (TNF alpha) was less effective. This system also p rovides a useful means for examining the involvement of negative and p ositive changes of polyamines in the induction of cSAT and c-jun, a ge ne that participates in the control of cSAT expression. a-Difluorometh ylornithine (DFMO) pretreatment, by lowering putrescine and spermidine in HGF- or IL-1 beta-treated cells, prevented the induction of cSAT. This effect was reversed by exogenous putrescine or spermidine. IL-1 b eta induced c-jun mRNA more than HGF. DFMO prevented almost completely the enhancement of c-jun mRNA expression by IL-1 beta, and this effec t was reversed by exogenous putrescine or spermidine. Therefore, we su ggest that cSAT and c-jun expression is specifically regulated by poly amine-mediated mechanisms in IL-1 beta treated HepG2 cells. Since cSAT is inducible by cytokines that control tumor metabolism and growth as well as tumor-host interaction, we hypothesize an involvement of cSAT in hepatoma growth. (C) 1998 Wiley-Liss, Inc.