Effect of progesterone and first evidence about allopregnanolone action on the progression of epithelial human ovarian cancer cell lines

Abstract

Ovarian carcinoma is one of the most common cause of death by gynecologic cancer. Several epidemiological and in vitro studies have shown controversial data about progesterone effects in ovarian cancer. Progesterone can be converted in its active metabolite, allopregnanolone, its effects in ovarian cancer are still unknown. Previously, we demonstrated that allopregnanolone modifies ovarian morphophysiology, being able to alter critical process of tumor development such as proliferation, apoptosis and angiogenesis. Taking into account these antecedents, we investigated the effect of progesterone and allopregnanolone on proliferation, apoptosis, clonogenic capacity and migration on two epithelial human ovarian cancer cell lines, IGROV-1 and SKOV-3. To this end, IGROV-1 and SKOV-3 cells were exposed to a range of progesterone and allopregnanolone concentrations (10-11 to 10-5 M) for 72 h. Proliferation was analyzed by MTT and Ki67 expression. Apoptosis was measured by immunocytochemistry of cleaved caspase 3. Clonogenic capacity was evaluated by counting colonies. Migration was analyzed by wound assay. We found that allopregnanolone increased proliferation and Ki67 expression respect to control on IGROV-1 cells, while expression of cleaved caspase 3 did not change in any cell line studied. IGROV-1 clonogenic capacity was also increased by allopregnanolone treatment. Both steroids, progesterone and allopregnanolone, increased IGROV-1 migration in a concentration dependent manner. None of the steroids tested modified SKOV-3 biological behavior analized. This is the first evidence that allopregnanolone, a progesterone metabolite, affects critical events in tumor development of human epithelial ovarian cancer. These results could have an impact in the future in clinic diagnosis, prognosis and treatment of ovarian cancer patients. The regulation of progesterone and allopregnanolone steroideogenesis and their molecular mechanisms might be considered as potential therapeutic tool in ovarian cancer.