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Differential Expression of FOXO1 and FOXO3a Confers Resistance to Oxidative Cell Death upon Endometrial Decidualization

Institute of Reproductive and Developmental Biology (T.K., M.J., L.F., M.T., F.F.-Z., G.P., H.M., J.J.B.), and Cancer Research-UK Labs and Section of Cancer Cell Biology (E.W.-F.L.), Department of Oncology, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom; Department of Obstetrics and Gynaecology (J.M.H.), Imperial College London, St. Mary’s Hospital, London W2 1PG, United Kingdom; and Department of Obstetrics and Gynecology (O.I.), Saitama Medical School, Moroyama, Saitama 350-0495, Japan

Address all correspondence and requests for reprints to: Jan J. Brosens, Institute of Reproductive and Developmental Biology, Imperial College London, Faculty of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom. E-mail: j.brosens{at}imperial.ac.uk.

The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy.

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