Abstract
Objective. Progesterone (P4) has been implicated as a protective factor for ovarian and endometrial cancers, yet little is known about its mechanism of action. We have shown apoptosis in ovarian and endometrial cancer cells with high doses of P4. Increased generation of reactive oxygen species (ROS) and an altered redox status have long been observed in cancer cells. The goal of this study was to assess the effect of P4 on cell growth, ROS generation, oxidative stress markers, and the expression of antioxidant proteins.
Methods. All experiments were performed in vitro using cancer cell lines. Cell proliferation was determined using MTS proliferation assay. Production of ROS in cells was measured with the ROS indicator dye, aminophenyl fluorescein. Alterations in expression of antioxidant and apoptotic proteins were assessed by Western blotting.
Results. The exposure of ovarian and endometrial cancer cell cultures to various doses of P4 caused a dose-dependent decrease in cell viability and the activation of caspase-3. Levels of ROS, markers of oxidative stress, and antioxidant proteins were elevated in cancer cells compared to normal cells and a marked decrease in their expression was seen following P4 treatment. In cancer cells, ROS was elevated while p-53 expression was low. P4 exposure of cells resulted in increased p-53 and BAX and decreased BCL-2 expression.
Conclusions. The data indicates that P4 has antioxidant effects. It alleviates ROS stress and causes apoptosis by upregulating proapoptotic (p-53 and BAX) and decreasing antiapoptotic (BCL-2) gene expression in cancer cells. These findings could have potential therapeutic implications.
Acknowledgments
We thank Dr. Satoru Kyo, Kanazawa University, School of Medicine, Kanazawa, Japan, for providing immortalized normal epithelial endometrial cells and Dr. Samuel C. Mok, Department of Gynecologic Oncology, M.D. Anderson Cancer Center, Houston, Texas, for providing the HOSE and OVCA cell lines. This study was supported, in part, by NIH Grant CA091250 (to V.S.). The opinions and assertions expressed herein are those of the authors and should not be construed as reflecting those of the Uniformed Services University of the Health Sciences or the U.S. Department of Defense.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.