Growth factor-mediated altered expression and regulation of S-adenosylmethionine decarboxylase in a H-ras transformed cell line capable of malignant progression.

Abstract

Mammalian S-adenosylmethionine decarboxylase (SAMDC) is a regulatory activity, which is involved in the biosynthesis of polyamines. The polyamines, namely putrescine, spermidine, and spermine, are essential for mammalian cell proliferation. SAMDC expression was examined in a H-ras transformed cell capable of metastasis formation. Serum stimulation of these cells resulted in increased SAMDC mRNA and enzyme activity expression. The effect of several physiologically relevant growth factors on SAMDC expression was also determined. SAMDC mRNA expression was increased in response to epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) stimulation but was unaffected by transforming growth factor beta(1) (TGF-beta(1)) and platelet derived growth factor (PDGF). Increased SAMDC enzyme activity occurred in response to exposure to EGF, bFGF, TGF-beta(1), and PDGF. The EGF and bFGF mediated alterations in SAMDC mRNA expression were apparently not due to alterations in the transcriptional apparatus but occurred partly through post-transcriptional mechanisms involving increased SAMDC message stability. EGF and bFGF were able both to cooperate with cycloheximide, an inhibitor of protein synthesis, to augment the expression of SAMDC mRNA. Furthermore, studies with NIH-3T3 fibroblasts transfected with either the normal basic fibroblast growth factor coding sequence that lacks a known secretory signal sequence or a chimeric bFGF sequence that targets the growth factor to the secretory pathway revealed that increased SAMDC expression occurred only in those cells which contained the chimeric bFGF sequence that targets the growth factor to the secretory pathway suggesting that the increase in expression of SAMDC occurs through an autocrine mechanism. Increased ornithine decarboxylase (ODC) expression was found to occur in both types of bFGF transfected cells suggesting that altered ODC expression in response to bFGF stimulation may occur through both autocrine and intracrine mechanisms. In addition, a correlation was found to exist between SAMDC expression and regulation in response to growth factor stimulation and malignant potential. This correlation supports the view that growth factor induced alterations in SAMDC expression, although not sufficient on their own to induce metastasis, are important in the promotion and establishment of events important to the phenotype expressed by H-ras transformed cells capable of malignant progression.