Role of ornithine decarboxylase in the regulation of cell growth by IL-1 and tumor necrosis factor.
Ornithine decarboxylase (ODC) is a rate-limiting enzyme in polyamine synthesis, and polyamines are required for cell growth. As an approach to clarifying the mechanism of action IL-1, the effects of IL-1 on ODC activity were examined in various cell lines whose proliferation was either suppressed or enhanced by IL-1. The proliferation of all cell types used in these experiments was markedly suppressed by a specific ODC inhibitor, alpha-difluoromethyl ornithine (DFMO), substantiating the crucial role of ODC activity for cell proliferation. ODC activity also was considerably suppressed by IL-1 in those cells on which IL-1 exerts an antiproliferative effect, such as a human melanoma cell line (A375) and malignant human mammary cell lines (MCF-7 and T-47D). On the other hand, ODC activity was stimulated in cells that are stimulated to proliferate in response to IL-1, such as a mouse helper T cell line (D10.G4.1), a NK cell-like cell line (YT), and a human glioblastoma cell line (U373 MG). The effect of IL-1 on ODC activity preceded and directly correlated in a dose-dependent manner with its effect on DNA synthesis. Furthermore, putrescine, a product of the ODC reaction and a precursor of polyamines, was able to overcome most, but not all, the antiproliferative action of IL-1 in A375 melanoma cells, which were the most sensitive to suppression by IL-1. However, putrescine did not reverse the cytostatic effect of IL-1 on MCF-7 and T-47D cell lines. In contrast, putrescine, like IL-1, exhibited some co-mitogenic activity on D10.G4.1 cells. Because the biological activities of TNF and IL-1 show considerable overlap, the effect of TNF on ODC activity also was examined. TNF had an antiproliferative effect on A375 cells and stimulated the proliferation of U373 MG cells. The ODC activity in A375 cells was suppressed by TNF, and the ODC activity in U373 MG cells was stimulated by TNF. Putrescine also partially overcame the inhibitory effect of TNF. These results suggest that the regulation of ODC activity may be a key component in the antiproliferative and proliferative action of IL-1 and TNF in some tumor cell types.
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Laboratory of Molecular Immunoregulation, National Cancer Institute, Frederick, MD 21701-1013.
Matsushima
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K
Onozaki
K
K
Oppenheim
J J
JJ
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D004247:DNA / Q000096:biosynthesis; D000518:Eflornithine / Q000494:pharmacology; D005910:Glioma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology* / Q000502:physiology; D008545:Melanoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009955:Ornithine Decarboxylase / Q000502:physiology*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000096:biosynthesis; D011700:Putrescine / Q000494:pharmacology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D006131:Growth Inhibitors; D007375:Interleukin-1; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D009955:Ornithine Decarboxylase; D011700:Putrescine; D000518:Eflornithine