Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The
SLUG
promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological factors in promoting stem-like properties in breast cancer cells. Thus, the LDHA-lowering agent vitamin C can be a potential approach for combating stress-associated breast cancer.
MicroRNA-210 (miRNA-210) has been reported to be associated with angiogenesis and may serve important roles in acute myocardial infarction (AMI), which remain unclear. The present study sought to evaluate the efficacy of miRNA-210 in AMI and to examine the potential associated mechanisms. AMI models were established in Sprague-Dawley rats. The expression of miRNA-210 was upregulated via transfection with lentivirus-mediated agonists and quantitative analysis was performed using the reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Immunoblotting and RT-qPCR were separately used to detect the expression levels of hepatocyte growth factor (HGF) in heart samples, while only the protein expression level of β-myosin heavy chain (β-MHC) was assessed. The expression of HGF in human umbilical vein endothelial cells under hypoxic conditions was silenced by transfecting with small interfering RNA, as demonstrated by the determination of associated protein expression levels. The microvessel density (MVD) of the infarcted myocardium was selected to be the angiogenesis efficacy endpoint, which was evaluated by platelet endothelial cell adhesion molecule immunostaining. Markedly increased expression of HGF was observed among the AMI rats receiving miRNA-210 agonists, demonstrated via quantitative analyses using RT-qPCR or western blotting. Promotion of angiogenesis was observed with the increased MVD. Improved cardiac function in the rats was subsequently noted, as they exhibited improved left ventricular fractional shortening and left ventricular ejection fraction percentages, which may result from improved cardiac contractility indicated by attenuating the increase in β-MHC protein expression. Overexpression of miRNA-210 appeared to be an advantageous therapeutic tool for treating AMI, primarily due to its promoting effects on angiogenesis in the infarcted myocardium by stimulating HGF expression and inducing improved left ventricular remodeling, leading to improved cardiac function.
Uncoupled endothelial nitric oxide synthase (eNOS) produces O instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.