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AG 205, a Progesterone Receptor Membrane Component 1 Antagonist, Ablates Progesterone's Ability to Block Oxidative Stress-Indu

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AG 205, a Progesterone Receptor Membrane Component 1 Antagonist, Ablates Progesterone's Ability to Block Oxidative Stress-Indu Biology of Reproduction, 2017, 96(4), 843–854 doi:10.1093/biolre/iox013 Research Article Advance Access Publication Date: 23 March 2017 Research Article AG 205, a progesterone receptor membrane component 1 antagonist, ablates progesterone’s ability to block oxidative stress-induced apoptosis of human granulosa/luteal cells† Erica Anspach Will2,3, Xiufang Liu1 and John J. Peluso2,∗ 1Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA; 2Department of Obstetrics and Gynecology, University of Connecticut Health Center, Farmington, Connecticut, USA and 3The Center for Advanced Reproductive Services, Farmington Connecticut, USA ∗Correspondence: Department of Cell Biology, University of CT Health Center, 263 Farmington Ave., Farmington, CT 06030, USA. Tel: 1-860-679-2860; Fax: 1-860-679-1269; E-mail: [email protected] †Grant Support: This project was supported by UCONN Health and the Department of Cell Biology Received 6 January 2017; Revised 31 January 2017; Accepted 21 March 2017 Abstract The present studies were designed to determine whether progesterone (P4)-progesterone receptor membrane component 1 (PGRMC1) signaling is able to attenuate the apoptotic effects of oxidative stress induced by hydrogen peroxide (H2O2). To achieve this goal, freshly isolated human gran- ulosa/luteal cells were maintained in culture. After several passages, the cells were treated with H2O2, which induced apoptosis within 2.5 h, while simultaneous treatment with P4 attenuated the apoptotic action of H2O2. AG 205, a PGRMC1 antagonist, eliminated P4’s ability to prevent H2O2- induced apoptosis. AG 205 neither affected PGRMC1’s cytoplasmic localization nor its interaction with PGRMC2, but appeared to reduce its presence within the nucleus. AG 205 also (1) increased the monomeric and decreased the higher molecular weight forms of PGRMC1 (i.e., dimers/oligomers) and (2) altered the expression of several genes involved in apoptosis. The most dramatic change was an approximate 8-fold increase in Harakiri (Hrk) mRNA. However, AG 205 did not induce apop- tosis in the absence of H2O2. Taken together, these observations suggest that the higher molecular weight forms of PGRMC1 likely account in part for PGRMC1’s ability to suppress the expression of Hrk. Harakiri is a BH-3 only member of the B-cell lymphoma 2 (BCL2) family that promotes apoptosis by binding to and antagonizing the antiapoptotic action of BCL2- and BCL2-like proteins. It is likely then that PGRMC1’s ability to suppress Hrk is part of the mechanism through which P4-PGRMC1 signaling preserves the viability of human granulosa/luteal cells. Summary Sentence The PGRMC1 antagonist, AG 205, blocks the ability of P4 to inhibit H2O2-induced apoptosis by disrupting PGRMC1 dimers/oligomers and inducing the expression of the apoptosis inducing BH3- only protein, Harakiri. Key words: apoptosis, granulosa cells, PGRMC1, PGRMC2, progesterone. C The Authors 2017. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. 843 For permissions, please e-mail: [email protected] Downloaded from https://academic.oup.com/biolreprod/article-abstract/96/4/843/3079300 by Univ of Connecticut user on 23 January 2018 844 E. A. Will et al., 2017, Vol. 96, No. 4 Introduction weight forms of PGRMC1 could have different functions, we opted to assess the effect of AG 205, which allows PGRMC1 to remain Progesterone (P4) plays an essential role in regulating female repro- within the cell. ductive function and fertility, influencing components of the entire reproductive axis [1, 2]. In the ovary, the best-defined role for P4 is its requirement for ovulation [3]. In primates, P4’s requirement Materials and methods for ovulation is revealed through the use of drugs, which inhibit its synthesis [4]. In mice, the genetic ablation of the classic nuclear Human granulosa/luteal cell isolation, culture, receptor (PGR) conclusively demonstrates that P4 mediates its ef- and propagation fect on ovulation through this receptor because these mutant mice The process for granulosa/luteal cell isolation and culture has been do not ovulate [3]. In addition to ovulation, P4 plays an essential detailed in our previous studies [13]. Briefly, follicular aspirates were role in the formation and maintenance of the corpus luteum. This is collected from patients undergoing in vitro fertilization at the Center an extremely important aspect of P4’s intraovarian function, since for Advanced Reproductive Services at the University of Connecticut the premature demise of the corpus luteum leads to the reduction Health Center. Samples were deidentified, thereby precluding any in serum P4 levels and ultimately the failure of implantation and/or link to clinical information. As such the institutional review board premature termination of pregnancy [5, 6]. Progesterone’s antiapop- of the University of Connecticut Health Center declared that this totic action is also observed in the granulosa cells of various sized protocol was exempt as it was considered nonhuman research. follicles [7] and luteinizing granulosa cells of the preovulatory folli- Once the oocytes were removed, the follicular aspirates were cle [4]. Interestingly, human chorionic gonadotropin (hCG) induces transported to the research laboratory where the follicular fluid was luteinizing granulosa cells within the preovulatory follicle of non- centrifuged and the cell pellet aspirated, resuspended in phosphate- human primates to undergo apoptosis if P4 synthesis is inhibited buffered saline (PBS), and layered with Histopaque-1077 gradient using trilostane [4]. The apoptotic action of hCG/trilostane is over- (catalog number 10771; Sigma-Aldrich). Following centrifugation come by supplemental progestin. Thus, P4’s antiapoptotic effect on at 400× g for 30 min [9, 14], the cohesive band of cells within the luteinizing granulosa cells is essential for the formation of the corpus Histopaque was pipetted onto an inverted 40-μm cell strainer (cata- luteum [4]. log number 08-771-1; Fisher Scientific) overlying a 50-ml tube [15]. As luteinization progresses, serum gonadotropins induce the ex- The aspirate was washed once with PBS to remove macrophages, pression of steroidogenic genes [8], thereby increasing P4 levels, lymphocytes, and monocytes. The strainer was then properly posi- which function to maintain the viability of luteal cells [9]. This posi- tioned into a new 50-ml tube and washed with PBS. The fluid was tive feedback mechanism is in effect until the late luteal phase, when centrifuged at 250× g for 10 min and the pellet resuspended in PBS. the capacity of the luteal cells to respond to gonadotropins is re- After additional two centrifugations, the isolated granulosa/luteal duced, P4 synthesis decreases and the luteal cells undergo apoptosis ◦ cell pellet was resuspended in 0.5% trypsin and incubated at 37 C [4]. The mechanism responsible for the decreased sensitivity to go- for 10 min, followed by the addition of fetal bovine serum (FBS)- nadotropins has not been clearly defined and may be due to a putative supplemented medium to stop the reaction, and a final centrifugation increase in ovarian prostaglandin F2α [10]. Importantly, the reduced at 250× g for 10 min. The pellet was resuspended in Dulbecco mod- ability to respond to gonadotropins is not the only factor that leads ified Eagle medium supplemented with 1% ITS (insulin-transferrin- to luteal cell death, because luteal cells are also exposed to apoptotic selenium; catalog number I3146; Sigma-Aldrich), 0.01% gentam- factors during the mid to late luteal phase of the menstrual cycle. icin (catalog number G1397; Sigma-Aldrich), and 10% FBS. Cells One such factor is reactive oxygen species (ROS) that are generated from individual patients were cultured on Matrigel (catalog number by leukocytes that invade the corpus luteum [10, 11]. 354230; BD Bioscience)-coated T-25 culture flasks until they were With the decline in P4 during the menstrual cycle and the increas- confluent. These cells were then harvested, pooled, and maintained in ing apoptotic effects of the ROS, the luteal cells undergo apoptosis culture. After five to eight passages, the cells were frozen and stored and the corpus luteum gradually regresses. If conception occurs, in liquid nitrogen for use in all subsequent experiments. As needed, then the corpus luteum is maintained even in the presence of ROS human granulosa/luteal cells were thawed and cultured in Matrigel- death-inducing activity. This is achieved by hCG, which is derived coated T-25 or T-75 culture flasks. When confluent, the cells were from the trophoblasts of the implanting embryo and acts to increase harvested and plated on non-Matrigel-coated culture dishes for Steroidogenic acute regulatory protein (StAR) expression and ulti- 24–48 h prior to any treatment. Cells were discarded after 13 mately P4 synthesis [12]. This increase in P4 could potentially block passages. the ROS-activated apoptotic pathway. Thus, determining whether P4 can attenuate these apoptotic pathways is absolutely critical for defining the mechanism involved in the maintenance of the corpus Microplate reader-based assay for cell viability luteum. To this end, we isolated granulosa/luteal cells from women Granulosa/luteal cells were harvested and counted using a hemacy- undergoing in vitro fertilization. These cells were maintained in cul- tometer. These cells were subsequently plated in a 96-well black, ture for several passages and then used in a series of experiments clear-bottomed plate at a density of 5 × 104 in 100 μl of steroid-free to determine whether P4 can inhibit ROS (e.g., hydrogen peroxide; serum (catalog number 30068-03; Thermo Scientific)-supplemented H2O2)-induced human granulosa/luteal cell apoptosis. In addition, medium and cultured overnight. In our initial attempt to identify the present studies extend our previous work in which progesterone cells undergoing apoptosis [16, 17], cells were fixed and stained receptor membrane component 1 (PGRMC1) siRNA attenuated P4’s with Annexin V-CY3 per the manufacturer’s recommendations (cat- antiapoptotic actions in human granulosa/luteal cells [9]byusing alog number K102-35; Biovision).
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