Expanding the roles for pregnane X receptor in cancer: Proliferation and drug resistance in ovarian cancer
Expanding the roles for pregnane X receptor in cancer: Proliferation and drug resistance in ovarian cancer
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DOI：
10.1158/1078-0432.ccr-08-1033
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发表时间：
2008-09-01
影响因子：
11.5
通讯作者：
Mani, Sridhar
中科院分区：
文献类型：
--
作者：
Gupta, Divya;Venkatesh, Madhukumar;Mani, Sridhar
目的：我们研究的存在下，卵巢癌细胞激活后，其同源ligand.Experimental设计：SKOV-3和OVCAR-8卵巢癌细胞的PXR的表达进行了分析，通过定量逆转录-PCR和蛋白质印迹法。还通过免疫化学分析了人卵巢癌组织的PXR表达。通过定量逆转录-PCR分析SKOV-3细胞中配体（激动剂）诱导的PXR靶基因。MTT法检测SKOV-3细胞增殖;在携带SKOV-3异种移植物的NOD.SCID小鼠中进行PXR配体的体外作用的体内确认。在SKOV-3细胞中，PXR是功能性的，其通过同源配体的激活诱导PXR靶基因（CYP 2B 6、CYP 3A 4和UGT 1A 1），但不诱导MDR 1和MRP 2。SKOV-3细胞中的PXR活化诱导细胞增殖和耐药性。在携带SKOV-3异种移植物的小鼠中，利福平（PXR激动剂）诱导细胞增殖和肿瘤growth.Conclusion：PXR激活，无论配体激动剂的类型，促进癌细胞的“恶性”表型。这些数据作为基础，寻找新的无毒抑制剂的PXR激活作为一种方法，以控制细胞生长和防止诱导耐药性。
Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand.Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western blot. Human ovarian cancer tissue was also analyzed for PXR expression by immunochemistry. Ligand (agonist)induced PXR target genes were analyzed in SKOV-3 cells by quantitative reverse transcription-PCR. SKOV-3 cell proliferation was assessed by MTT assay. In vivo confirmation of in vitro effects of PXR ligands were done in NOD.SCID mice carrying SKOV-3 xenografts.Results: PXR is expressed in ovarian cancer cells. In SKOV-3 cells, PXR is functional and its activation by cognate ligands induces PXR target genes (CYP2B6, CYP3A4, and UGT1A1) but not MDR1 and MRP2. PXR activation in SKOV-3 cells induces cell proliferation and drug resistance. In mice harboring SKOV-3 xenografts, rifampicin (PXR agonist) induces cell proliferation and tumor growth.Conclusion: PXR activation, regardless of the type of ligand agonist present, promotes the "malignant" phenotype of cancer cells. These data serve as the basis for finding novel nontoxic inhibitors of PXR activation as a method to control cell growth and prevent induction of drug resistance.