ABSTRACT
Non-small cell lung cancers (NSCLCs) demonstrate intrinsic resistance to cell death, even after chemotherapy. Previous work suggested defective nuclear translocation of active caspase-3 in observed resistance to cell death. We have identified mitogen-activated protein kinase-activated protein kinase 2 (MK2; encoded by the gene MAPKAPK2) is required for caspase-3 nuclear translocation in the execution of apoptosis in endothelial cells. The objective was to determine MK2 expression in NSCLCs and the association between MK2 and clinical outcomes in patients with NSCLC. Clinical and MK2 mRNA data were extracted from two demographically distinct NSCLC clinical cohorts, North American (The Cancer Genome Atlas, TCGA) and East Asian (EA). Tumor responses following first round of chemotherapy were dichotomized as clinical response (complete response, partial response, and stable disease) or progression of disease. Multivariable survival analyses were performed using Cox proportional hazard ratios and Kaplan-Meier curves. NSCLC exhibited lower MK2 expression than SCLC cell lines. In patients, lower tumor MK2 transcript levels were observed in those presenting with late-stage NSCLC. Higher MK2 expression was associated with clinical response following initial chemotherapy and independently associated with improved 2-yr survival in two distinct cohorts, 0.52 (0.28-0.98) and 0.1 (0.01-0.81), TCGA and EA, respectively, even after adjusting for common oncogenic driver mutations. Survival benefit of higher MK2 expression was unique to lung adenocarcinoma when comparing across various cancers. This study implicates MK2 in apoptosis resistance in NSCLC and suggests prognostic value of MK2 transcript levels in patients with lung adenocarcinoma.
Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Caspase 3/therapeutic use , Endothelial Cells , Lung Neoplasms/drug therapy , Lung Neoplasms/geneticsABSTRACT
We have previously identified mitogen-activated protein kinase-activated protein kinase 2 (MK2) is required for caspase-3 nuclear translocation in the execution of apoptosis; however, little is known of the underlying mechanisms. Therefore, we sought to determine the role of kinase and nonkinase functions of MK2 in promoting nuclear translocation of caspase-3. We identified two non-small cell lung cancer cell lines for use in these experiments based on low MK2 expression. Wild-type, enzymatic and cellular localization mutant MK2 constructs were expressed using adenoviral infection. Cell death was evaluated by flow cytometry. In addition, cell lysates were harvested for protein analyses. Phosphorylation of caspase-3 was determined using two-dimensional gel electrophoresis followed by immunoblotting and in vitro kinase assay. Association between MK2 and caspase-3 was evaluated using proximity-based biotin ligation assays and co-immunoprecipitation. Overexpression of MK2 resulted in nuclear translocation of caspase-3 and caspase-3-mediated apoptosis. MK2 directly phosphorylates caspase-3; however, phosphorylation status of caspase-3 or MK2-dependent phosphorylation of caspase-3 did not alter caspase-3 activity. The enzymatic function of MK2 was dispensable in nuclear translocation of caspase-3. MK2 and caspase-3 associated together and a nonenzymatic function of MK2, chaperoned nuclear trafficking, is required for caspase-3-mediated apoptosis. Taken together, our results demonstrate a nonenzymatic role for MK2 in the nuclear translocation of caspase-3. Furthermore, MK2 may function as a molecular switch in regulating the transition between the cytosolic and nuclear functions of caspase-3.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Apoptosis , Caspase 3/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: The COVID-19 pandemic disrupted routine school operations, including school health programs. This study aims to describe the pandemic's impact on school health service delivery from the perspective of Maryland school health partners. METHODS: We conducted semi-structured interviews with health service representatives from public schools (K-12) between July and December 2021. Interviews were recorded, transcribed, and coded through an iterative process to develop analytic themes. RESULTS: Twenty school health partners from 15 Maryland school districts participated. Participants identified key impacts of COVID-19 on school health: (1) COVID-19 disrupted delivery of services such as dental, mental health, and preventative care, (2) COVID-19 necessitated changes in service delivery platforms, (3) COVID-19 affected school health staff through increased responsibilities and staffing shortages, and (4) COVID-19 prompted schools to become hubs for community outreach and health education. IMPLICATIONS FOR SCHOOL HEALTH POLICY, PRACTICE, AND EQUITY: Consideration of school health service disruptions and the increased demands on service providers may inform future priorities for school administrators, health departments, and policymakers. CONCLUSIONS: COVID-19 impacted the timing and method of service delivery as well as the roles of school health staff and schools themselves in public health and education.
Subject(s)
COVID-19 , School Health Services , Humans , COVID-19/epidemiology , Maryland , School Health Services/organization & administration , SARS-CoV-2 , Child , Schools/organization & administration , Interviews as Topic , AdolescentABSTRACT
Introduction: Although factors such as urbanicity, population demographics, and political affiliation have been linked with COVID-19 masking behavior and policy in community settings, little work has investigated factors associated with school mask policies. We sought to characterize United States state and school district student COVID-19 masking policies during the 2021-22 school year and determine predictors of these mandates at four time points, including before and after federal guidance relaxed school mask recommendations in February 2022. Methods: Student mask policies for US states and the District of Columbia, as well as a sample of 56 districts were categorized as prohibited, recommended, or required in September 2021, November 2021, January 2022, and March 2022 based on the Johns Hopkins eSchool+ Initiative School Reopening Tracker. Changes in policies over time were characterized. Generalized estimating equations and logistic regression were used to evaluate whether political affiliation of governor, urbanicity, economic disadvantage, and race/ethnic composition of district students, and county-level COVID-19 incidence predicted the presence of a district mask mandate at any time point and at all four time points. Results: State and district policies changed over time. Districts that implemented student mandates at any point were more likely to be in states with Democratic governors (AOR: 5.52; 95% CI: 2.23, 13.64) or in non-rural areas (AOR: 8.20; 95% CI: 2.63, 25.51). Districts that retained mask mandates at all four time points were more likely to have Democratic governors (AOR: 5.39; 95% CI: 2.69, 10.82) and serve a smaller proportion of economically disadvantaged students (AOR: 0.97; 95% CI: 0.95, 0.99). Districts serving a larger proportion of students from minoritized racial/ethnic groups were more likely to have mask mandates at any or all timepoints. Notably, county-level COVID-19 prevalence was not related to the presence of a mask mandate at any or all time points. By March 2022, no factors were significantly associated with district mask policy. Discussion: Political, geographic, and demographic characteristics predicted the likelihood of student mask mandates in the 2021-22 school year. Public health promotion messages and policy must account for variation in these factors, potentially through centralized and consistent messaging and unbiased, trustworthy communication.