Demonstration of mixed properties of RU486 in progesterone receptor (PR)-transfected MDA-MB-231 cells: a model for studying the functions of progesterone analogues.
Progesterone antagonist RU486 (mifepristone) has been implicated for many anti-neoplastic and obstetrical applications. But the compound has demonstrated undesired agonist-like effect depending on cell, tissue and species studied. Using PR-transfected breast cancer cells MDA-MB-231, this report describes the similarities and differences between progesterone- and RU486-mediated effects on cell growth, cell differentiation and, at the molecular level, on the activation of p44/p42 MAP kinases (MAPK). Like progesterone, RU486 inhibited cells growth by arresting the cells in G0/G1 phase of the cell cycle. In contrast to progesterone that induced cell spreading, RU486 induced a multipolar, stellate morphology. RU486-treated cells showed no increase of stress fibers, nor was there any increase of focal adhesions as progesterone-treated cells did. Furthermore, despite of the fact that both compounds inhibited cell growth, RU486 significantly stimulated the activation of p44/p42 MAP kinases whereas progesterone markedly inhibited the activation. Nonetheless, the effects of RU486 were PR-mediated and RU486 was able to antagonize the effect of progesterone on cell growth and focal adhesion. In conclusion, RU486 can act not only as a progesterone antagonist, a progesterone agonist but also induced morphological and molecular changes that were distinct from progesterone-mediated effects in PR-transfected MDA-MB-231 cells. The non-progesterone-like effect of RU486 may be mediated through a pathway that is different from the progesterone-mediated pathway, or it is the result of a blockade of certain critical step(s) in the progesterone-mediated pathway. In any case, undesired side effects of antiprogestin may create clinical complications. PR-transfected MDA-MB-231 breast cancer cells provide a model for studying the functions of progesterone analogues.
Lin
V C
VC
Department of Clinical Research, Singapore General Hospital, Republic of Singapore 169608.
Aw
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SE
Ng
E H
EH
Ng
E H
EH
Tan
M G
MG
D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D015735:Mifepristone / Q000494:pharmacology*; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000187:drug effects; D022502:Stress Fibers / Q000648:ultrastructure; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D006067:Gonanes; D006727:Hormone Antagonists; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D015735:Mifepristone; D011374:Progesterone; C053238:onapristone