Tamoxifen resistance is accountable for relapse in many ER-positive breast cancer patients. Most of these recurrent patients receive chemotherapy, but their chemosensitivity is unknown. Here, we report that tamoxifen-resistant breast cancer cells express significantly more BARD1 and BRCA1, leading to resistance to DNA-damaging chemotherapy including cisplatin and adriamycin, but not to paclitaxel. Silencing BARD1 or BRCA1 expression or inhibition of BRCA1 phosphorylation by Dinaciclib restores the sensitivity to cisplatin in tamoxifen-resistant cells. Furthermore, we show that activated PI3K/AKT pathway is responsible for the upregulation of BARD1 and BRCA1. PI3K inhibitors decrease the expression of BARD1 and BRCA1 in tamoxifen-resistant cells and re-sensitize them to cisplatin both in vitro and in vivo. Higher BARD1 and BRCA1 expression is associated with worse prognosis of early breast cancer patients, especially the ones that received radiotherapy, indicating the potential use of PI3K inhibitors to reverse chemoresistance and radioresistance in ER-positive breast cancer patients.

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Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes.

MicroRNAs (miRNAs), a class of small noncoding RNAs that regulate target gene expression, play an important role in cancer initiation, progression, and metastasis. However, the role of many miRNAs in cervical cancer is not fully understood. In this study, we found that miR-212 and miR-132 from the same gene cluster are downregulated in human cervical cancer tissues when compared with adjacent noncancerous tissues. The overexpression of miR-212/132 not only led to a delay in the G1/S phase transition and repressed cell proliferation but also resulted in an increase in E-cadherin expression and a decrease in vimentin, suppressing the epithelial to mesenchymal transition and migration and invasion in cervical cancer cells. Subsequently, SMAD2 was identified as a common target of miR-212/132 and was found to be negatively regulated by miR-212/132 at the mRNA and protein levels. Furthermore, SMAD2 silencing led to the same effect on cervical cancer cells as miR-212/132 overexpression. Importantly, SMAD2 overexpression partially reversed the cellular phenotypes induced by miR-212/132 overexpression. In conclusion, our study indicated that miR-212/132 functions as tumor suppressor by targeting SMAD2 in cervical cancer. V C 2015 IUBMB Life, 67(5): [380][381][382][383][384][385][386][387][388][389][390][391][392][393][394] 2015

Background The inhaled anesthetic sevoflurane has been demonstrated to protect against myocardial ischemia/reperfusion (MI/R) injury, via mechanisms involving AMP-activated protein kinase (AMPK) and caveolin-3 (Cav-3). However, the relative contributions of AMPK and Cav-3 to sevoflurane preconditioning-mediated cardioprotection, and their precise underlying mechanisms of action, remain incompletely understood. Methods and Results Sevoflurane preconditioning (SF-PreCon, consisting of 3 cycles of 15 minute-exposures to 2% sevoflurane prior to 30 minutes of MI) decreased MI/R injury in WT mice (caspase-3 activity −29.1%, infarct size −20.2%, and LVEDP −33.8%). In cardiac-specific AMPKα2 dominant negative overexpression (AMPK-DN) mice, the cardioprotective effect of SF-PreCon was largely retained (caspase-3 activity −26.7%, infarct size −16.7%, and LVEDP −25.9%, P<0.01). In contrast, SF-PreCon failed to significantly protect Cav3-knockout (Cav3-KO) mice against MI/R injury (P>0.05). SF-PreCon significantly decreased MI/R-induced superoxide generation in WT (−43.6%) and AMPK-DN mice (−35.5%, P<0.01), but not in Cav3-KO mice. SF-PreCon did not affect NADPH oxidase expression, but significantly inhibited COX-2 expression in WT (−38.7%) and AMPK-DN mice (−35.8%), but not in Cav-3KO mice. Conclusions We demonstrate for the first time sevoflurane preconditioning mediates cardioprotection against MI/R injury via Cav-3 dependent-COX-2 inhibition and anti-oxidative effects.