Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models
| Autor: | Risa Akizuki, Ryohei Maruhashi, Akira Ikari, Yasuhiro Yamazaki, Hideki Sakai, Toshiyuki Matsunaga, Tomonari Sato, Satoshi Endo, Masahiko Yamaguchi |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lung Neoplasms endocrine system diseases Adenocarcinoma of Lung Adenocarcinoma digestive system 03 medical and health sciences 0302 clinical medicine Spheroids Cellular Humans Claudin-2 Cytotoxicity Claudin Molecular Biology Cell Proliferation A549 cell Cell Nucleus Gene knockdown urogenital system Cell growth Chemistry Multidrug resistance-associated protein 2 Gefitinib Cell Biology digestive system diseases Multidrug Resistance-Associated Protein 2 Gene Expression Regulation Neoplastic 030104 developmental biology A549 Cells Doxorubicin Drug Resistance Neoplasm 030220 oncology & carcinogenesis Paracellular transport Cancer cell Cancer research Quinazolines Cisplatin Multidrug Resistance-Associated Proteins tissues |
| Zdroj: | Biochimica et biophysica acta. Molecular cell research. 1865(3) |
| ISSN: | 0167-4889 |
| Popis: | Claudins, tight junctional proteins, regulate the paracellular permeability of ions and small molecules. Claudin-2 is highly expressed in human lung adenocarcinoma cells and is involved in the up-regulation of cell proliferation. However, the effect of claudin-2 on cellular sensitivity to anticancer agents has not been clarified. The cytotoxicity of anticancer agents such as cisplatin, gefitinib and doxorubicin (DXR) was increased by claudin-2 knockdown in A549 cells. Claudin-2 knockdown also significantly decreased the expression level of multidrug resistance-associated protein/ABCC2. The expression levels of other drug efflux transporters were unchanged. The intracellular accumulation of 5-chloromethylfluorescein diacetate (CMFDA) and DXR, substrates of ABCC2, was increased by claudin-2 knockdown, whereas the efflux was decreased. MK-571, an inhibitor of ABCC2, enhanced the cytotoxicity of anticancer agents. Claudin-2 knockdown decreased the levels of p-c-Jun and nuclear Sp1. SP600125, an inhibitor of c-Jun, and mithramycin, an inhibitor of Sp1, decreased the level of ABCC2. The promoter activity of ABCC2 was decreased by claudin-2 knockdown, SP600125 and mithramycin treatments, suggesting that claudin-2 is involved in the up-regulation of ABCC2 expression at the transcriptional level. Claudin-2 knockdown increased the paracellular permeability of DXR in a 2D monolayer culture model. In addition, the accumulation of DXR into spheroids was enhanced by claudin-2 knockdown, resulting in a reduction in cell viability. We suggest that claudin-2 may be a novel therapeutic target in lung adenocarcinoma, because claudin-2 knockdown increased the accumulation of anticancer agents in cancer cells and spheroids. |
| Databáze: | OpenAIRE |
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