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

Abstract

BackgroundThe steroid and xenobiotic receptor, SXR, is an orphan nuclear receptor that regulates metabolism of diverse dietary, endobiotic, and xenobiotic compounds. SXR is expressed at high levels in the liver and intestine, and at lower levels in breast and other tissues where its function was unknown. Since many breast cancer preventive and therapeutic compounds are SXR activators, we hypothesized that some beneficial effects of these compounds are mediated through SXR.MethodsTo test this hypothesis, we measured proliferation of breast cancer cells in response to SXR activators and evaluated consequent changes in the expression of genes critical for proliferation and cell-cycle control using quantitative RT-PCR and western blotting. Results were confirmed using siRNA-mediated gene knockdown. Statistical analysis was by t-test or ANOVA and a P value ≤ 0.05 was considered to be significant.ResultsMany structurally and functionally distinct SXR activators inhibited the proliferation of MCF-7 and ZR-75-1 breast cancer cells by inducing cell cycle arrest at the G1/S phase followed by apoptosis. Decreased growth in response to SXR activation was 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 were preceded by an increase in inducible nitric oxide synthase and nitric oxide in these cells. Inhibition of iNOS blocked the induction of p53. p53 knockdown inhibited up-regulation of p21 and BAX. We infer that NO is required for p53 induction and that p53 is required for up-regulation of cell cycle regulatory and apoptotic genes in this system. SXR activator-induced increases in iNOS levels were inhibited by siRNA-mediated knockdown of SXR, indicating that SXR activation is necessary for subsequent regulation of iNOS expression.ConclusionWe conclude that activation of SXR is anti-proliferative in p53 wild type breast cancer cells and that this effect is mechanistically dependent upon the local production of NO and NO-dependent up-regulation of p53. These findings reveal a novel biological function for SXR and suggest that a subset of SXR activators may function as effective therapeutic and chemo-preventative agents for certain types of breast cancers.

Pregnane X receptor activation induces FGF19-dependent tumor aggressiveness in humans and mice

“…However our observations are in stark contrast to recent observations that PXR induces apoptosis in colon (60) and breast cancer (18) and predicts for significantly improved survival in esophageal cancer (61). The discrepancy is likely due to methodological differences.…”

“…This promiscuous xenosensor plays a central role in regulating liver and gastrointestinal drug metabolism. However, PXR is widely expressed in many different tissues and tumors (e.g., colon, breast, and ovary) (15)(16)(17)(18)(19). In search of tissue-specific functions of PXR, we previously demonstrated that PXR activation induces ovarian cancer cell proliferation and drug resistance (20).…”

Pregnane X receptor suppresses proliferation and tumourigenicity of colon cancer cells

“…Wan and colleagues reported the mouse lacking PXR showed decreased liver regeneration after partial hepatectomy and the PXR-regulated lipid homoeostasis, which fuels the liver regeneration, may have a role in the suppressed liver growth (Dai et al, 2008). Verma et al (2009) reported that PXR activation induced apoptosis in breast cancer cell line and PXR is anti-proliferative and the effect is mechanistically dependant on the local production of NO and NO-dependent upregulation of p53. As the HT29 cells have mutated p53, the mechanism of PXR-regulated inhibitory effects on HT29 growth may differ from the NO-dependent upregulation of p53 reported.…”

Novel acylated steroidal glycosides from Caralluma tuberculata induce caspase-dependent apoptosis in cancer cells

“…Pregnane glycosides are structurally similar to cardiac glycosides such as digoxin (Deepak et al 1997), which inhibit calcium exchangers, thereby leading to a prolonged increase in intracellular calcium concentration and stimulation of caspases and apoptosis. Another possible mechanism of action is the activation of the steroid and xenobiotic receptor (SXR), an orphan steroid receptor, which induces apoptosis in breast cancer cells (Verma et al 2009). Further studies are required, but the activation of the SXR is an exciting possibility.…”