Purpose: Targeting the protein neddylation pathway has become an attractive anticancer strategy; however, the role of death receptor-mediated extrinsic apoptosis during treatment remained to be determined.Experimental Design: The activation of extrinsic apoptosis and its role in MLN4924 treatment of human esophageal squamous cell carcinoma (ESCC) were evaluated both in vitro and in vivo. The expression of the components of extrinsic apoptotic pathway was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies.Results: Pharmaceutical or genetic inactivation of neddylation pathway induced death receptor 5 (DR5)-mediated apoptosis and led to the suppression of ESCC in murine models. Mechanistically, neddylation inhibition stabilized activating transcription factor 4 (ATF4), a Cullin-Ring E3 ubiquitin ligases (CRL) substrate. Transcription factor CHOP was subsequently transactivated by ATF4 and further induced the expression of DR5 to activate caspase-8 and induce extrinsic apoptosis. Moreover, the entire neddylation pathway was hyperactivated in ESCC and was negatively associated with patient overall survival.Conclusions: Our findings highlight a critical role of ATF4-CHOP-DR5 axis-mediated extrinsic apoptosis in neddylationtargeted cancer therapy and support the clinical investigation of neddylation inhibitors (e.g., MLN4924) for the treatment of ESCC, a currently treatment-resistant disease with neddylation hyperactivation.
BackgroundBurnout is a health problem in nurses. Individuals with a certain personality are more susceptible to job-related burnout. General self-efficacy (GSE) is an important predictor of job-related burnout. The relationships between general self-efficacy, job-related burnout and different personality types are still not clear. This study aims to analyze the relationships of job-related burnout, stress, general self-efficacy and personality types, as well as their interactions in job-related burnout.MethodA cross-sectional survey of 860 nurses was conducted between June and July 2015 in China. We measured their job-related burnout using the scale of the Maslach Occupational Burnout Scale, and personality, stress, and GSE. Machine learning of generalized linear model were performed.ResultsMaslach Burnout Inventory (MBI) professional efficacy was significantly associated with gender, marital status, age, job title and length of service. A machine learning algorithm showed that stress was the most important factor in job-related burnout, followed by GSE, personality type (introvert unstable), and job title. Individuals with low GSE and either introversion or unstable (high neuroticism) personality seemed to have stronger burnout when they faced stress (regardless of stress intensity) compared to others.ConclusionStress, GSE and introvert unstable personality are the top three factors of job-related burnout. GSE moderates the effect of stress on burnout in nurses with extroversion or neuroticism personality. Reducing stress, increasing GSE, and more social support may alleviate job-related burnout in nurses. Nurses with introvert unstable personality should be given more social support in reducing stress and enhancing their GSE.Electronic supplementary materialThe online version of this article (10.1186/s12913-018-3478-y) contains supplementary material, which is available to authorized users.
The sphingomyelin-ceramide pathway is an evolutionarily conserved ubiquitous signal transduction system that regulates many cell functions including apoptosis. Sphingomyelin (SM) is hydrolyzed to ceramide by different sphingomyelinases. Ceramide serves as a second messenger in mediating cellular effects of cytokines and stress. In this study, we find that acid sphingomyelinase (SMase) activity was induced by UVA in normal JY lymphoblasts but was not detectable in MS1418 lymphoblasts from Niemann-Pick type D patients who have an inherited deficiency of acid SMase. We also provide evidence that UVA can induce apoptosis by activating acid SMase in normal JY cells. In contrast, UVA-induced apoptosis was inhibited in MS1418 cells. Exogenous SMase and its product, ceramide (10 -40 M), induced apoptosis in JY and MS1418 cells, but the substrate of SMase, SM (20 -80 M), induced apoptosis only in JY cells. These results suggest that UVA-induced apoptosis by SM is dependent on acid SMase activity. We also provide evidence that induction of apoptosis by UVA may occur through activation of JNKs via the acid SMase pathway.
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.