Abstract
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.
Highlights
Xenobiotic metabolism has been described as an adaptive response utilized by organisms exposed to drugs or environmental chemicals leading to induction of drug metabolizing enzymes to enhance water solubility and excretion [1]
Similar results were seen in HCT116 human colon cancer and LS180 intestinal human colon adenocarcinoma cells by overexpressing constitutively activated pregnane X receptor (PXR) or through pharmacologic activation of PXR with the cognate ligand rifampicin [35], suggesting an anti-apoptotic role of PXR in carcinogenesis
In other hormone-dependent neoplasms such as prostate cancer, Chen and colleagues [32] found that PXR activation by the selective potent agonist SR12813 enhanced resistance to chemotherapeutic drugs taxol and vinblastine via PXR-mediated upregulation of cytochrome P450 enzyme 3A4 (CYP3A4) and multidrug resistance protein-1 (MDR1) in human prostate cancer PC3 cells
Summary
Xenobiotic metabolism has been described as an adaptive response utilized by organisms exposed to drugs or environmental chemicals leading to induction of drug metabolizing enzymes to enhance water solubility and excretion [1]. Similar results were seen in HCT116 human colon cancer and LS180 intestinal human colon adenocarcinoma cells by overexpressing constitutively activated PXR or through pharmacologic activation of PXR with the cognate ligand rifampicin [35], suggesting an anti-apoptotic role of PXR in carcinogenesis.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
