RRC ID 55911
Author Maruhashi R, Akizuki R, Sato T, Matsunaga T, Endo S, Yamaguchi M, Yamazaki Y, Sakai H, Ikari A.
Title Elevation of sensitivity to anticancer agents of human lung adenocarcinoma A549 cells by knockdown of claudin-2 expression in monolayer and spheroid culture models.
Journal Biochim Biophys Acta Mol Cell Res
Abstract 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.
Volume 1865(3)
Pages 470-479
Published 2018-3-1
DOI 10.1016/j.bbamcr.2017.12.005
PII S0167-4889(17)30320-8
PMID 29247669
MeSH A549 Cells Adenocarcinoma / drug therapy* Adenocarcinoma / genetics* Adenocarcinoma / pathology Adenocarcinoma of Lung Cell Nucleus / genetics Cell Proliferation / drug effects Cisplatin / administration & dosage Claudin-2 / antagonists & inhibitors Claudin-2 / genetics* Doxorubicin / administration & dosage Drug Resistance, Neoplasm / genetics* Gefitinib Gene Expression Regulation, Neoplastic Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics* Lung Neoplasms / pathology Multidrug Resistance-Associated Protein 2 Multidrug Resistance-Associated Proteins / genetics Quinazolines / administration & dosage Spheroids, Cellular / drug effects
IF 4.739
Times Cited 8
Human and Animal Cells A549