Tissue-specific regulation of pregnane X receptor in cancer development and therapy.
Tissue-specific regulation of pregnane X receptor in cancer development and therapy.
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DOI：
10.1186/2045-3701-4-17
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发表时间：
2014-04-01
影响因子：
7.5
通讯作者：
Chen T
中科院分区：
文献类型：
--
作者：
Robbins D;Chen T
作为核激素受体超家族中的配体依赖性转录因子，PXR具有调节外源性物质和胆固醇代谢、能量稳态、肠道粘膜防御和癌症发展等多种功能。尽管PXR的解毒功能已被广泛研究和确立，但PXR在癌症中的作用仍存在争议。由于超过60%的非处方药和处方药通过细胞色素P450酶3A 4（CYP 3A 4）（PXR的转录靶点）代谢，因此对新型治疗方式全身给药期间PXR调控的深入了解将有助于更好地了解PXR在人类疾病背景下的功能。先前的研究表明，PXR活化主要通过上调CYP 3A 4和多药耐药蛋白-1（MDR 1）降低某些结肠癌的药物敏感性并增加其耐药性。后来的研究表明，PXR表达的下调可能是致癌性的激素依赖性乳腺癌和子宫内膜癌通过减少雌激素代谢通过CYP 3A 4;因此，较高的雌二醇浓度有助于致癌作用。这些结果表明PXR在肿瘤生长调节中的不同作用取决于组织类型和肿瘤微环境。在这里，我们将总结PXR用于诱导其对癌组织的不同影响的各种机制。此外，目前的方法将被探索，以评估利用PXR介导的途径作为一种新的机制的方法来治疗癌症。
As a ligand-dependent transcription factor of the nuclear hormone receptor superfamily, the pregnane X receptor (PXR) has a multitude of functions including regulating xenobiotic and cholesterol metabolism, energy homeostasis, gut mucosal defense, and cancer development. Whereas the detoxification functions of PXR have been widely studied and well established, the role of PXR in cancer has become controversial. With more than 60% of non-prescription and prescription drugs being metabolized by cytochrome P450 enzyme 3A4 (CYP3A4), a transcriptional target of PXR, insights into the regulation of PXR during systemic administration of novel treatment modalities will lead to a better understanding of PXR function in the context of human disease. Previous studies have suggested that PXR activation decreases drug sensitivity and augments chemoresistance in certain colon cancers mainly through the upregulation of CYP3A4 and multidrug resistance protein-1 (MDR1). Later studies suggest that downregulation of PXR expression may be oncogenic in hormone-dependent breast and endometrial cancers by reducing estrogen metabolism via CYP3A4; thus, higher estradiol concentrations contribute to carcinogenesis. These results suggest a differential role of PXR in tumor growth regulation dependent on tissue type and tumor microenvironment. Here, we will summarize the various mechanisms utilized by PXR to induce its diverse effects on cancerous tissues. Moreover, current approaches will be explored to evaluate the exploitation of PXR-mediated pathways as a novel mechanistic approach to cancer therapy.
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影响因子：
3
作者：
Harmsen, Stefan;Meijerman, I.;Febus, C. L.;Maas-Bakker, R. F.;Beijnen, J. H.;Schellens, J. H. M.
通讯作者：
Schellens, J. H. M.
影响因子：
3.6
作者：
Duret, Cedric;Daujat-Chavanieu, Martine;Gerbal-Chaloin, Sabine
通讯作者：
Gerbal-Chaloin, Sabine
影响因子：
5.8
作者：
Chen, Yakun;Tang, Yong;Guo, Changxiong;Wang, Jiuhui;Boral, Debasish;Nie, Daotai
通讯作者：
Nie, Daotai
DOI：
10.1073/pnas.95.21.12208
发表时间：
1998-10-13
影响因子：
11.1
作者：
Bertilsson, G;Heidrich, J;Berkenstam, A
通讯作者：
Berkenstam, A
影响因子：
3.9
作者：
Healan-Greenberg, Christine;Waring, Jeffrey F.;Kim, Richard B.
通讯作者：
Kim, Richard B.