Dissociation of tumour-promoter-induced effects on prostaglandin release, polyamine synthesis and cell proliferation of 3T3 cells

Abstract

The phorbol ester 12-O-tetradecanoylphorbol-13-acetate [TPA] induces tumor promotion, inflammation, cell proliferation and prostaglandin release. Addition of TPA (1 .mu.M to 1 nM) to confluent mouse 3T3 fibroblasts successively caused the release of prostaglandins [PG] E2 and I2, induction of the enzyme ornithine decarboxylase (EC 4.1.1.17), stimulation of [3H]thymidine incorporation into DNA and cell proliferation. Pretreatment of the cells with the anti-inflammatory steroid dexamethasone (1 .mu.M) or the non-steroidal anti-inflammatory drug indomethacin (1 .mu.M) inhibited TPA-induced prostaglandin release. Dexamethasone enhanced the other effects of TPA; indomethacin was ineffective. Addition of PGE2 to the cultures did not induce ornithine decarboxylase activity and cell proliferation. Pretreatment of the cells with 1,3-diaminopropane (1 mM) or .alpha.-methylornithine (5 mM), inhibitors of polyamine synthesis, decreased TPA-induced ornithine decarboxylase activity without affecting DNA synthesis. TPA stimulated [3H]thymidine incorporation into DNA, even when the ornithine decarboxylase activity was completely blocked. The proliferating effect of TPA on 3T3 cells apparently is independent of PG release and polyamine synthesis.