The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction
The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction
复制标题
DOI：
10.1096/fj.07-8688com
复制
发表时间：
2007-11-01
期刊：
影响因子：
4.8
通讯作者：
Keelan, J. A.
中科院分区：
文献类型：
--
作者：
Evseenko, Denis A.;Murthi, Padma;Keelan, J. A.
外排泵 ATP 结合盒超家族成员 G2 (ABCG2)/乳腺癌抗性蛋白 (BCRP) 在人胎盘中高度表达。我们研究了 BCRP 在保护人胎盘滋养层免于凋亡中的作用及其在特发性胎儿生长受限（一种与胎盘异常凋亡相关的疾病）中的表达。用选择性抑制剂 Ko143 抑制 BCRP 活性可增强原代滋养层细胞和滋养层样 BeWo 细胞中细胞因子（肿瘤坏死因子-α/干扰素-γ）诱导的细胞凋亡和磷脂酰丝氨酸外化。 BeWo 细胞中 BCRP 表达的沉默显着增加了细胞因子和外源性 C6 和 C8 神经酰胺对细胞凋亡损伤的敏感性。 BCRP 沉默还增加了细胞因子暴露后细胞内神经酰胺的水平，但不影响细胞原卟啉 IX 浓度或对内在凋亡途径激活剂的敏感性。与对照组相比，并发特发性胎儿生长受限的妊娠胎盘中 BCRP 表达降低，表明其底物从胎盘的转运减少。我们得出的结论是，BCRP 可能在胎盘中发挥迄今为止未被认识的生存作用，通过调节神经酰胺信号传导保护滋养层免受细胞因子诱导的细胞凋亡和可能的其他外在激活剂的影响。胎盘 BCRP 表达减少可能导致活力降低，从而导致功能缺陷，导致胎儿生长受限表型。
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-alpha/interferon-gamma)-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.