Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.
Progesterone receptor membrane component 1 deficiency attenuates growth while promoting chemosensitivity of human endometrial xenograft tumors.
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DOI：
10.1016/j.canlet.2014.09.036
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发表时间：
2015-01-28
期刊：
影响因子：
9.7
通讯作者：
Pru, James K.
中科院分区：
文献类型：
--
作者：
Friel, Anne M.;Zhang, Ling;Pru, Cindy A.;Clark, Nicole C.;McCallum, Melissa L.;Blok, Leen J.;Shioda, Toshi;Peluso, John J.;Rueda, Bo R.;Pru, James K.
子宫内膜癌是美国女性的主要妇科癌症，预计2014年有52，630名女性被诊断患有这种疾病。本研究的目的是确定孕激素（P4）受体膜成分1（PGRMC 1）是否影响子宫内膜癌细胞活力，在体外和体内化疗反应。基于Jentiviral的shRNA敲低方法用于产生稳定的PGRMC 1完整和PGRMC 1缺失的石川子宫内膜癌细胞系，其也缺乏经典孕酮受体（PGR）的表达。PGRMC 1-完整细胞的有丝分裂被抑制，而PGRMC 1-缺失细胞的有丝分裂被抑制，表明PGRMC 1介导P4的抗有丝分裂作用。为了检验PGRMC 1减弱化疗诱导的细胞凋亡的假设，PGRMC 1-完整细胞和PGRMC 1-缺失细胞在体外用载体、P4（1 μM）、阿霉素（Dox. 2 μg/ml）。或P4 + Dox 48 h。阿霉素处理PGRMC 1-完整细胞导致细胞死亡显著增加;然而，与P4共同处理显著减弱了Dex诱导的细胞死亡。这种对P4的反应在PGRMC 1缺失的细胞中丧失。为了在体内扩展这些观察结果，采用异种移植模型，其中分别在皮下和腹膜内接种免疫受损的NOD/Scio和裸鼠后产生PGRMC 1完整和PGRMC 1耗尽的子宫内膜肿瘤。来源于PGRMC 1耗尽细胞的肿瘤比来源于PGRMC 1完整细胞的肿瘤生长得慢。然后对携带子宫内膜肿瘤的小鼠进行三次溶剂（1：1 Cremophor EL：乙醇+0.9%盐水）或化疗[紫杉醇（15 mg/kg，腹腔注射）]治疗然后间隔30分钟后给予卡铂（50 mg/kg）]，间隔5天。在对化疗的反应中，与PGRMC 1完整对照肿瘤相比，PGRMC 1耗尽肿瘤的肿瘤体积减少约4倍，表明PGRMC 1在化疗应激期间促进肿瘤细胞活力。总之，这些体外和体内研究结果表明，PGRMC 1在人子宫内膜肿瘤的生长和化疗耐药性中起着重要作用。
Endometrial cancer is the leading gynecologic cancer in women in the United States with 52,630 women predicted to be diagnosed with the disease in 2014. The objective of this study was to determine if progesterone (P4) receptor membrane component 1 (PGRMC1) influenced endometrial cancer cell viability in response to chemotherapy in vitro and in vivo. A Jentiviral-based shRNA knockdown approach was used to generate stable PGRMC1-intact and PGRMC1-deplete Ishikawa endometrial cancer cell lines that also lacked expression of the classical progesterone receptor (PGR). Progesterone treatment inhibited mitosis of PGRMC1-intact, but not PGRMC1-deplete cells, suggesting that PGRMC1 mediates the anti-mitotic actions of P4.To test the hypothesis that PGRMC1 attenuates chemotherapy-induced apoptosis, PGRMC1-intact and PGRMC1-deplete cells were treated in vitro with vehicle, P4 (1 μM), doxorubicin (Dox. 2 μg/ml). or P4 + Dox for 48 h. Doxorubicin treatment of PGRMC1-intact cells resulted in a significant increase in cell death; however, co-treatment with P4 significantly attenuated Dex-induced cell death. This response to P4 was lost in PGRMC1-deplete cells. To extend these observations in vivo, a xenograft model was employed where PGRMC1-intact and PGRMC1-deplete endometrial tumors were generated following subcutaneous and intraperitonea l inoculation of immunocompromised NOD/SCIO and nude mice, respectively. Tumors derived from PGRMC1-deplete cells grew slower than tumors from PGRMC1-intact cells. Mice harboring endometrial tumors were then given three treatments of vehicle (1:1 cremophor EL: ethanol + 0.9% saline) or chemotherapy [Paclitaxel (15 mg/kg, i.p.) followed after an interval of 30 minutes by CARBOplatin (SO mg/kg)] at five day intervals. In response to chemotherapy, tumor volume decreased approximately four-fold more in PGRMC1-deplete tumors when compared with PGRMC1 intact control tumors, suggesting that PGRMC1 promotes tumor cell viability during chemotherapeutic stress. In sum, these in vitro and in vivo findings demonstrate that PGRMC1 plays a prominent role in the growth and chemoresistance of human endometrial tumors.
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