CONCOMITANT CHANGES IN POLYAMINE POOLS AND DNA METHYLATION DURING GROWTH-INHIBITION OF HUMAN COLONIC-CANCER CELLS

The effects of CGP 48664 and DFMO, selective inhibitors of the key enz ymes of polyamine biosynthesis, namely, of S-adenosylmethionine decarb oxylase (AdoMetDC) and ornithine decarboxylase (ODC), were investigate d on growth, polyamine metabolism, and DNA methylation in the Caco-2 c ell line, Both inhibitors caused growth inhibition and affected simila rly the initial expression of the differentiation marker sucrase. In t he presence of the AdoMetDC inhibitor, ODC activity and the intracellu lar pool of putrescine were enhanced, whereas the spermidine and sperm ine pools were decreased. In the presence of the ODC inhibitor, the Ad oMetDC activity was enhanced and the intracellular pools of putrescine and spermidine were decreased. With both compounds, the degree of glo bal DNA methylation was increased, Spermine and spermidine (but not pu trescine) selectively inhibited cytosine-DNA methyltransferase activit y. Our observations suggest that spermidine (and to a lesser extent sp ermine) controls DNA methylation and may represent a crucial step in t he regulation of Caco-2 cell growth and differentiation. (C) 1998 Acad emic Press.