Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response

Abstract

Pregnane xenobiotic receptor (PXR) is an orphan nuclear receptor that regulates the metabolism of endobiotics and xenobiotics. PXR is promiscuous and unique in that it is activated by a diverse group of xenochemicals, including therapeutic anticancer drugs and naturally-occurring endocrine disruptors. PXR has been predominantly studied to understand its regulatory role in xenobiotic clearance in liver and intestine via induction of drug metabolizing enzymes and drug transporters. PXR, however, is widely expressed and has functional implications in other normal and malignant tissues, including breast, prostate, ovary, endometrium and bone. The differential expression of PXR and its target genes in cancer tissues has been suggested to determine the prognosis of chemotherapeutic outcome. In addition, the emerging evidence points to the implications of PXR in regulating apoptotic and antiapoptotic as well as growth factor signaling that promote tumor proliferation and metastasis. In this review, we highlight the recent progress made in understanding the role of PXR in cancer, discuss the future directions to further understand the mechanistic role of PXR in cancer, and conclude with the need to identify novel selective PXR modulators.

Tumor Suppressor Protein p53 Negatively Regulates Human Pregnane X Receptor Activity

“…In colon cancer cells, expression of wild-type p53 induces apoptosis (Shaw et al, 1992), whereas activation of PXR induces colon tumor growth and malignancy (Wang et al, 2011;Mani et al, 2013;Pondugula and Mani, 2013). In this study, we showed that in colon cancer cell line HCT116, wildtype p53 downregulates PXR activity.…”

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation

“…Highly expressed in the liver and intestinal epithelium, the PXR has been previously characterized as a master regulator of xenobiotic metabolism and clearance (Watkins et al, 2002;Staudinger et al, 2006;Shukla et al, 2011;Dou et al, 2013;Pondugula and Mani, 2013). Acting as a sensor of exogenous chemicals, the PXR's activation leads to the expression of a variety of target genes related to detoxification and efflux pathways.…”

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

“…Threonine-290 Regulates Human PXR Nuclear Translocation Discussion PXR, a member of the nuclear receptor superfamily, was originally characterized as a xenobiotic-activated transcription factor that plays a key role in regulating the expression of genes encoding drugmetabolizing enzymes and drug transporters. It was subsequently found to potentiate various biologic effects associated with pharmacologic and toxicologic consequences-not only the metabolism and clearance of endobiotics and xenobiotics, including various therapeutic drugs and environmental endocrine disruptors, but also cancer pathogenesis (Timsit and Negishi, 2007;Staudinger and Lichti, 2008;Ihunnah et al, 2011;Pondugula and Mani, 2013) and hepatic energy metabolism including gluconeogenesis, the b-oxidation of fatty acids, and lipogenesis (Konno et al, 2008). PXR is activated by the binding of endogenous and exogenous xenobiotics to its ligand-binding domain and is then translocated to the nucleus in which it activates transcription by binding to the xenobiotic-response element in the promoter region of the target gene with RXR (Timsit and Negishi, 2007).…”