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The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction

Denis A. Evseenko^*, Padma Murthi, James W. Paxton, Glen Reid, B. Starling Emerald^*, K. M. Mohankumar^*, Peter E. Lobie^*, Shaun P. Brennecke, Bill Kalionis and J. A. Keelan^*,,1

^* Liggins Institute, University of Auckland, Auckland, New Zealand;

Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand;

Genesis Research and Development Corporation, Auckland, New Zealand; and

Pregnancy Research Centre, Department of Perinatal Medicine, The Royal Women’s Hospital and Department of Obstetrics and Gynaecology, The Royal Women’s Hospital and University of Melbourne, Carlton, Victoria, Australia

¹Correspondence: Liggins Institute and Department of Pharmacology and Clinical Pharmacology, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: j.keelan{at}auckland.ac.nz

The efflux pump ATP binding cassette superfamily member G2 (ABCG2)/breast cancer resistance protein (BCRP) is highly expressed in human placenta. We have investigated the role of BCRP in the protection of the human placental trophoblasts from apoptosis and its expression in idiopathic fetal growth restriction, a condition associated with abnormal placental apoptosis. Inhibition of BCRP activity with the selective inhibitor Ko143 augmented cytokine (tumor necrosis factor-/interferon-)-induced apoptosis and phosphatidylserine externalization in primary trophoblast and trophoblast-like BeWo cells. Silencing of BCRP expression in BeWo cells significantly increased their sensitivity to apoptotic injury in response to cytokines and exogenous C6 and C8 ceramides. BCRP silencing also increased intracellular ceramide levels after cytokine exposure but did not affect cellular protoporphyrin IX concentrations or sensitivity to activators of the intrinsic apoptotic pathway. BCRP expression in placentas from pregnancies complicated by idiopathic fetal growth restriction was decreased compared with controls, suggesting reduced transport of its substrates from the placenta. We conclude that BCRP may play a hitherto unrecognized survival role in the placenta, protecting the trophoblast against cytokine-induced apoptosis and possibly other extrinsic activators via modulation of ceramide signaling. Decreased placental BCRP expression may result in reduced viability and hence functional deficit, contributing to the fetal growth restriction phenotype.—Evseenko, D. A., Murthi, P., Paxton, J. W., Reid, G., Emerald, B. S., Mohankumar, K. M., Lobie, P. E., Brennecke, S. P., Kalionis, B. Keelan, J. A. The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction.

Key Words: breast cancer resistance protein • cytokines • ceramide

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