The progesterone antagonist RU486 acquires agonist activity upon stimulation of cAMP signaling pathways.

摘要: Abstract The protein kinase A stimulator cAMP can potentiate the ability of progestins to induce transactivation function human progesterone receptor (hPR). We questioned in present study whether could functionally cooperate with progestin antagonist RU486. In T47D breast cancer cells, RU486 behaves as a pure respect induction progesterone-responsive mouse mammary tumor virus chloramphenicol acetyltransferase (MMTV-CAT) reporter gene. It fails stimulate MMTV-CAT expression and completely inhibits by synthetic R5020. However, when is combined 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP), induced levels approaching that stimulated R5020 alone. Also, presence 8-Br-cAMP only partially effective antagonizing action. The agonist activity exhibited under these conditions appears be due acting through hPR evidenced fact alone has no effect on MMTV-CAT, whereas combination dose responsive saturable manner inhibited type I antiprogestin (prevents hPR-DNA binding) ZK98299, which does not exhibit positive functional cooperation cAMP. Acquisition also extends II (permits ZK112993. Since antagonist, results suggest detection synergism between antiprogestins may require binding hPR-antagonist complex DNA. propose cross-talk second messenger steroid signal transduction pathways one mechanism for resistance antagonists frequently develops cancer.