Pregnane xenobiotic receptor in cancer pathogenesis and therapeutic response

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.

► PXR is an orphan nuclear receptor that is activated by both endobiotics and xenobiotics, including anticancer drugs.
► PXR has been implicated in chemoresistance and in tumor growth, promotion, and metastasis.
► PXR has been proposed as a therapeutic target in treating cancers.
► Identification of novel selective PXR modulators, particularly antagonists, would be beneficial to improve the therapeutic outcomes of PXR expressing cancers.