期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 2, 页码 742-759出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.68724
关键词
Pregnane nuclear receptor (PXR); post-translational modifications; protein-protein interactions; chemotherapeutic drug resistance
资金
- initiative fund for faculty development from Lanzhou University [561119203]
Pregnane x receptor (PXR) plays a crucial role in drug metabolism and also has pleiotropic functions in regulating inflammatory responses, glucose metabolism, and protecting normal cells against carcinogenesis. It can regulate gene expression at both the transcriptional and translational level and has a broad protein-protein interaction network that is involved in cross signaling pathways. Understanding how PXR maintains genome stability and prevents carcinogenesis can be beneficial for clinical diagnosis and treatment. Additionally, PXR contributes to chemotherapeutic drug resistance through the regulation of CYP450 enzymes and multidrug resistance proteins. Furthermore, this review discusses promising antagonists and their clinical applications in reversing chemoresistance.
Pregnane x receptor (PXR) as a nuclear receptor is well-established in drug metabolism, however, it has pleiotropic functions in regulating inflammatory responses, glucose metabolism, and protects normal cells against carcinogenesis. Most studies focus on its transcriptional regulation, however, PXR can regulate gene expression at the translational level. Emerging evidences have shown that PXR has a broad protein-protein interaction network, by which is implicated in the cross signaling pathways. Furthermore, the interactions between PXR and some critical proteins (e.g., p53, Tip60, p300/CBP-associated factor) in DNA damage pathway highlight its potential roles in this field. A thorough understanding of how PXR maintains genome stability and prevents carcinogenesis will help clinical diagnosis and finally benefit patients. Meanwhile, due to the regulation of CYP450 enzymes CYP3A4 and multidrug resistance protein 1 (MDR1), PXR contributes to chemotherapeutic drug resistance. It is worthy of note that the co-factor of PXR such as RXR alpha, also has contributions to this process, which makes the PXR-mediated drug resistance more complicated. Although single nucleotide polymorphisms (SNPs) vary between individuals, the amino acid substitution on exon of PXR finally affects PXR transcriptional activity. In this review, we have summarized the updated mechanisms that PXR protects the human body against carcinogenesis, and major contributions of PXR with its co-factors have made on multidrug resistance. Furthermore, we have also reviewed the current promising antagonist and their clinic applications in reversing chemoresistance. We believe our review will bring insight into PXR-targeted cancer therapy, enlighten the future study direction, and provide substantial evidence for the clinic in future.
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