Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States. Mortality rates for ovarian cancer have been unchanged for more than 70 years even though surgical and chemotherapeutic strategies have become considerably more sophisticated. While a lack of clinical success is largely due to a poor etiologic understanding, recent observations suggest that the ovarian steroid hormone progesterone may be an endogenous ovarian cancer tumor suppressor. Therefore, the goal of our studies was to define progesterone receptor action in ovarian cancer and identify the signaling mechanisms responsible for its tumor suppressive function.
Membrane progesterone receptors (mPRs) represent a newly defined class of ~40 kDa GPCR-like progesterone receptors belonging to the adipoQ receptor ( PAQR ) gene family. Never studied in cancerous cells of ovarian surface epithelial origin, we identified positive expression of each isoform (mPRα/PAQR7, mPRβ/PAQR8, and mPRγ/PAQR5) in a panel of ovarian cancer cell lines. Contrary to breast cancer cells, progesterone stimulation of these receptors in ovarian cancer cells increased intracellular cAMP levels and cAMP response element (CRE) transcriptional activity, but required high, pregnancy equivalent levels of progesterone as well as β 1,2 -adrenergic receptor co-stimulation. High-dose progesterone exposure also increased phosphorylation of the stress-activated JNK1/2 and p38 mitogen activated protein kinases (MAPKs). In particular, mPR-mediated p38 activation was responsible for increasing BAX mRNA expression; a pro-apoptotic Bcl family member. These results demonstrate that functionally active mPRs are capable of activating signaling pathways associated with tumor suppression in ovarian cancer cells.
Clinical observations have shown that nuclear progesterone receptor (PR) expression is downregulated as ovarian tumors become progressively more malignant. Overexpression of PR in the ES-2 ovarian cancer cell line inhibited cellular proliferation and increased cell survival. As a result, prolonged ligand stimulation caused PR-expressing cells to undergo cellular senescence and exit the cell-cycle into G 0 . Senescent cells expressed significantly higher mRNA levels of the cell-cycle inhibitor p21. When the inhibition of PR-induced p21 expression was removed by stably downregulating STAT3 expression, PR-mediated senescence occurred more quickly and p21 induction was enhanced as cells arrested in the G1 phase of the cell-cycle. However, when increased p21 expression was prevented, ligand-stimulated PR-expressing cells also exhibited a heightened senescence response. These findings, along with the observation that ligand-stimulated PR-positive primary human ovarian cancer cells also become senescent, support our conclusion that PR-mediated cellular senescence is an endogenous ovarian cancer tumor suppressive mechanism.
Taken together, these results demonstrate that progesterone receptors possess tumor suppressing characteristics in ovarian cancer cells, and warrant further investigation into the use of progesterone as an ovarian cancer chemopreventive and chemotherapeutic agent.
University of Minnesota Ph.D. dissertation. July 2010. Major: Microbiology, Immunology and Cancer Biology. Advisor: Lange, Carol A. 1 computer file (PDF); xi, 141 pages.
Charles, Nathan Jon.
Membrane and nuclear progesterone receptors activate tumor suppressive signaling mechanisms in cell line models of human ovarian cancer.
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