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

<p>Abstract</p> <p>Background</p> <p>The 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.</p> <p>Methods</p> <p>To 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.</p> <p>Results</p> <p>Many 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.</p> <p>Conclusion</p> <p>We 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.</p

Diabetes and Cardiovascular Care Among People with Severe Mental Illness: A Literature Review

Close to 19 million US adults have severe mental illnesses (SMI), and they die, on average, 25 years earlier than the general population, most often from cardiovascular disease (CVD). Many of the antipsychotic medications used to treat SMI contribute to CVD risk by increasing risk for obesity, type 2 diabetes, dyslipidemia, and hypertension. Based on compelling evidence, the American Diabetes Association and the American Psychiatric Association developed guidelines for metabolic screening and monitoring during use of these medications. In this manuscript, we have reviewed the evidence on diabetes and other CVD risk screening, prevalence, and management among populations with SMI. We also review differences in screening among subpopulations with SMI (e.g., racial/ethnic minorities, women, and children). We found that despite national guidelines for screening for diabetes and other cardiovascular risk factors, up to 70 % of people taking antipsychotics remain unscreened and untreated. Based on estimates that 20 % of the 19 million US adults with SMI have diabetes and 70 % of them are not screened; it is likely that over 2 million Americans with SMI have unidentified diabetes. Given that undiagnosed diabetes costs over $4,000 per person, this failure to identify diabetes among people with SMI represents a missed opportunity to prevent morbidity and translates to over$8 billion in annual preventable costs to our healthcare system. Given the high burden of disease and significant evidence of suboptimal medical care received by people with SMI, we propose several clinical and policy recommendations to improve diabetes and other CVD risk screening and care for this highly vulnerable population. These recommendations include reducing antipsychotic medication dose or switching antipsychotic medications, enhancing smoking cessation efforts, sharing electronic health records between physical and mental health care systems, and promoting integration of care

Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology

Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture