The high mortality rates associated with ovarian cancer are largely due to a lack of highly effective treatment options for advanced stage disease; a time when initial diagnosis most commonly occurs. Recent evidence suggests that the steroid hormone, progesterone, may possess anti-tumorigenic properties. With the discovery of a new class of membrane-bound progesterone receptors (mPRs) belonging to the progestin and adipoQ receptor (PAQR) gene family in the ovary, there are undefined mechanisms by which progesterone may inhibit tumor progression. Therefore, our goal was to define potential mPR-dependent signaling mechanisms operative in ovarian cancer cells. We detected abundant mPRα (PAQR7), mPRβ (PAQR8), and mPRγ (PAQR5), but not classical nuclear PR (A or B isoforms) mRNA expression and mPRα protein expression in a panel of commonly used ovarian cancer cell lines. In contrast to mPR action in breast cancer cells, progesterone alone failed to induce changes in cyclic adenosine monophosphate (cAMP) levels in ovarian cancer cells. However, progesterone enhanced cAMP production by β 1,2-adrenergic receptors and increased isoproterenol-induced transcription from a cAMP response element (CRE)-driven reporter gene. Independently of β-adrenergic signaling, we additionally observed activation of both JNK1/2 and p38 MAPK in response to progesterone alone. This finding was supported by the results of a screen for potential mPR gene targets. Progesterone induced a significant increase in transcription of the pro-apoptotic marker BAX, whose activity and expression has been linked to JNK1/2 and p38 signaling. Inhibitors of JNK, but not p38, blocked progesterone-induced BAX expression. Taken together, these observations implicate at least two distinct signaling pathways that may be utilized by mPRs in ovarian cancer cells that exhibit regulatory genomic changes. These studies on mPR signaling in ovarian cancer lay the foundation for future work aimed at understanding how progesterone exerts its anti-tumorigenic effects in the ovary and suggest that pharmacologic activation of mPRs, abundantly expressed in ovarian cancers, may provide a new treatment option for patients with advanced stage disease.
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Acknowledgements This work was supported by a grant from the Minnesota Ovarian Cancer Alliance. From the University of Minnesota Masonic Cancer Center, we would like to thank Dr. Douglas Yee, Dr. Amy Skubitz, and Dr. Sundaram Ramakrishnan for providing us with ovarian cancer cell line models and Dr. Paul Mermelstein for the CRE-luciferase reporter construct. We would also like to thank Dr. Patricia Kruk (University of South Florida) for providing us with the 1816-575 cell line.
- Jun kinase (JNK)
- Membrane progesterone receptor (mPR)
- Ovarian cancer
- p38 Mitogen-activated protein kinase