Activation of the steroid and xenobiotic receptor, SXR, induces apoptosis in breast cancer cells.

摘要

The steroid and xenobiotic receptor, SXR, is a broad-specificity orphan nuclear receptor which regulates metabolism of diverse xeno- and endobiotic compounds. SXR is expressed at high levels in the liver and intestine, and at lower levels in other tissues such as breast, where its function was unknown. In this study, we discovered a novel role for SXR as an inhibitor of breast cancer cell growth in estrogen receptor positive and p53 wild type breast cancer cell lines. Decreased growth of breast cancer cells in response to SXR activation is associated with stabilization of p53 and up-regulation of cell cycle regulatory and pro-apoptotic genes such as p21, PUMA and BAX. These gene expression changes are preceded by an increase in inducible nitric oxide synthase (iNOS) and nitric oxide (NO) in these cells. Inhibition of iNOS blocked the induction of p53, demonstrating that NO is required for p53 induction in this system. The SXR activator induced increase in iNOS was also inhibited by siRNA-mediated silencing of SXR, indicating that SXR activation both precedes, and is necessary for subsequent regulation of iNOS expression. Silencing of SXR also inhibited the apoptosis induced by SXR activators again confirming that SXR inhibits breast cancer growth and that this effect is mechanistically dependent upon the local production of NO and NO-dependent up-regulation of p53.;In this study, we also tested the effects of single nucleotide polymorphisms (SNPs) in SXR gene on its ability to inhibit the transcription factor NF-kappaB. NF-kappaB is a key modulator of immune and inflammatory response in body and also controls myriad of genes involved in cell survival and apoptosis pathways. SXR and NF-kappaB mutually inhibit each other. We found that SXR SNPs with decreased DNA binding ability had increased ability to repress NF-kappaB. The differences in the ability of SXR SNPs to inhibit NF-kappaB can indicate the inter-individual differences in susceptibility to cancers and auto-immune diseases. We also found that activation of protein kinase A pathway increases SXR activity while inhibits the activity of NF-kappaB indicating that PKA can be mechanistically involved in the mutual inhibition of SXR and NF-kappaB.