Regulation of drug resistance by human pregnane X receptor in breast cancer
Regulation of drug resistance by human pregnane X receptor in breast cancer
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DOI：
10.4161/cbt.8.13.8696
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发表时间：
2009-07-01
影响因子：
3.6
通讯作者：
Nie, Daotai
中科院分区：
文献类型：
--
作者：
Chen, Yakun;Tang, Yong;Nie, Daotai
耐药性是有效治疗乳腺癌的一个重要障碍。人妊娠X受体（Human pregnane X receptor, hPXR）是一种孤儿核受体，是细胞色素P450 3A4 （CYP3A4）等药物代谢酶（DMEs）和多药耐药基因（MDR1）等外排转运体的主要转录因子，被许多重要的临床药物激活。hPXR已在人类乳腺癌中被检测到，但其在癌症对药物反应中的作用仍不清楚。在本研究中，hPXR在乳腺癌细胞系以及正常和癌变的人乳腺标本中均有表达。SR12813在MDA-MB-231细胞中预激活hPXR，导致对浓度为20和50 nmol/L的紫杉醇的抗性增加。hPXR预激活的MCF-7对他莫昔芬的耐药性也显著增加。hPXR的激活导致CYP3A4和MDR1的表达增加，这两种可能是hPXR介导的乳腺癌耐药的介质。此外，通过小发夹RNA （shRNA）敲低hPXR使MDA-MB-231和MCF-7细胞对紫杉醇、长春花碱或他莫昔芬的治疗增敏。在癌症治疗药物的压力下，减少集落形成进一步证实了hPXR敲低细胞的耐药性降低。综上所述，我们的数据表明hPXR在乳腺癌对药物治疗的耐药性中具有潜在的作用。
Drug resistance is a significant barrier to an effective treatment of breast cancer. Human pregnane X receptor (hPXR), an orphan nuclear receptor known for its activation by many important clinical drugs, is a major transcription factor of drug metabolism enzymes (DMEs), such as cytochrome P450 3A4 (CYP3A4), and efflux transporters such as multi-drug resistance gene (MDR1). hPXR has been detected in human breast cancers but its role in responses of cancers toward drugs remains unknown. In this study, hPXR expression was confirmed in breast cancer cell lines and in normal and cancerous human breast specimens. Preactivation of hPXR by SR12813 in MDA-MB-231 cells led to an increased resistance to Taxol at concentrations of 20 and 50 nmol/L. A significant increase in resistance toward tamoxifen was also observed in MCF-7 with hPXR preactivation. Activation of hPXR led to an increased expression of CYP3A4 and MDR1, two possible mediators for hPXR-mediated drug resistance in breast cancers. Furthermore, knockdown of hPXR via small hairpin RNA (shRNA) sensitized MDA-MB-231 and MCF-7 cells to the treatment of Taxol, vinblastine or tamoxifen. The reduction in resistance of hPXR knockdown cells was further confirmed by reduced colony formation under the pressure of cancer treatment drugs. Taken together, our data suggest a potential role of hPXR in breast cancer resistance to drug treatments.