ABSTRACT
BACKGROUND: Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has been used as first-line treatment for advanced non-small-cell lung cancer (NSCLC). However, during treatment, cancer cells often develop resistance to gefitinib, the mechanisms of which are not fully understood. This study was designed to elucidate the expression and role of long non-coding RNA (lncRNA)-PCAT-1, a potential biomarker for drug resistance and a therapeutic target for NSCLC, in gefitinib resistance in NSCLC cells. METHODS: In this study, we verified differential PCAT-1 expression in NSCLC gefitinib-resistant tissues or cells. PCAT-1 knockdown, clone formation, Transwell, flow cytometry, and immunofluorescence assays were used to verify the correlation between PCAT-1 and gefitinib sensitivity. A nude mouse tumor-bearing model verified that PCAT-1 can reverse gefitinib resistance in vivo. Then, a PI3K/Akt agonist was used to verify the possible mechanism of PCAT-1 action. RESULTS: PCAT-1 is highly expressed in gefitinib-resistant NSCLC tissues and cells. PCAT-1 knockdown enhanced gefitinib sensitivity and gefitinib-induced apoptosis in H1299/GR cells. PCAT-1 knockdown reduced tumor volume and weight, and reversed acquired gefitinib resistance in vivo. PCAT-1 knockdown inhibited AKT and GSK3 phosphorylation in H1299/GR cells. A PI3K/AKT agonist reversed PCAT-1 knockdown-mediated enhancement of gefitinib sensitivity in H1299/GR cells CONCLUSION: PCAT-1 knockdown improves sensitivity to gefitinib by inhibition of AKT and GSK3 phosphorylation in NSCLC. PCAT-1 is as potential target for improving the clinical efficacy of gefitinib.
Subject(s)
Antineoplastic Agents/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Gefitinib/pharmacology , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , RNA, Long Noncoding/metabolism , Animals , Apoptosis/drug effects , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Glycogen Synthase Kinase 3/metabolism , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Mice, Nude , Phosphatidylinositol 3-Kinase/metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , RNA, Long Noncoding/genetics , Signal Transduction , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To study the effect of silverionized drinking water on erythrocyte membrane fluidity, serum lipids and vascular endothelial cells in tail-suspended rats. METHOD: Thirty male SD rats were randomly divided into ground control group (GC), simulated weightlessness control group (SC), simulated weightlessness and silverionized water drinking group (SS). Number of circulating endothelial cells (CEC), serum lipids and erythrocyte membranes fluidity was measured on the 21st day of tail suspension. RESULT: Levels of serum TC, TG, HDL-C, HDL-C/TC and erythrocyte membrane fluidity in SC rats were significantly lower than those in GC rats; LDL-C/HDL-C ratio and number of CEC in SC rats were markedly higher than those in GC rats. Levels of serum TC, LDL-C and LDL-C/HDL-C in SS rats were higher than those in SC rats; HDL-C/TC ratio and erythrocyte membrane fluidity in SS rats were lower than those in SC rats. CONCLUSION: Drinking silverionized water has a negative effect on lipid metabolism in tail-suspended rats.
Subject(s)
Cholesterol, HDL/drug effects , Cholesterol, LDL/drug effects , Silver/pharmacology , Water/pharmacology , Weightlessness Simulation , Animals , Cholesterol, HDL/metabolism , Cholesterol, LDL/metabolism , Endothelial Cells/drug effects , Hindlimb Suspension , Male , Membrane Fluidity , Rats , Rats, Sprague-Dawley , Triglycerides/metabolismABSTRACT
OBJECTIVE: To study the changes of erythrocyte membrane fluidity, serum lipid and vascular endothelial cell caused by simulated weightlessness in rats and the beneficial effect of spirulina. METHOD: Thirty male SD rats were divided into 3 groups: free control group (group A) and two simulated weightlessness groups (groups B, C). Rats in group A and B were fed with normal forage, and the rats in group C were fed with normal forage supplemented with 5% (W/W) spirulina. Water was taken ad libitum. RESULT: Levels of serum CHO, HDL, TG, HDL-C/CHO and erythrocyte membrane fluidity decreased significantly, and number of vascular endothelial cells in plasma increased markedly in group B as compared with those in group A; The ratio of LDL-C/HDL-C, and atherosclerosis index (AI) decreased, number of vascular endothelial cells significantly lowered; level of CHO, HDL-C and value of the IDmax of plasma as well as erythrocyte membrane fluidity remarkedly increased in group C compared with those in group B. CONCLUSION: Spirulina can improve the physiological conditions of erythrocyte membrane fluidity, serum lipid and vascular endothelial cell caused by simulated weightlessness in rats.
