RRC ID 55912
Author Akizuki R, Maruhashi R, Eguchi H, Kitabatake K, Tsukimoto M, Furuta T, Matsunaga T, Endo S, Ikari A.
Title Decrease in paracellular permeability and chemosensitivity to doxorubicin by claudin-1 in spheroid culture models of human lung adenocarcinoma A549 cells.
Journal Biochim Biophys Acta Mol Cell Res
Abstract Chemotherapy resistance is a major problem in the treatment of cancer, but the underlying mechanisms are not fully understood. We found that the expression levels of claudin-1 (CLDN1) and 3, tight junctional proteins, are upregulated in cisplatin (CDDP)-resistant human lung adenocarcinoma A549 (A549R) cells. A549R cells showed cross-resistance to doxorubicin (DXR). Here, the expression mechanism and function of CLDN1 and 3 were examined. CLDN1 and 3 were mainly localized at tight junctions concomitant with zonula occludens (ZO)-1, a scaffolding protein, in A549 and A549R cells. The phosphorylation levels of Src, MEK, ERK, c-Fos, and Akt in A549R cells were higher than those in A549 cells. The expression levels of CLDN1 and 3 were decreased by LY-294002, a phosphoinositide 3-kinase (PI3K) inhibitor, and BAY 11-7082, an NF-κB inhibitor. The overexpression of CLDN1 and 3 decreased the paracellular permeability of DXR in A549 cells. Hypoxia levels in A549R and CLDN1-overexpressing cells (CLDN1/A549) were greater than those in A549, mock/A549, and CLDN3/A549 cells in a spheroid culture model. In contrast, accumulation in the region inside the spheroids and the toxicity of DXR in A549R and CLDN1/A549 cells were lower than those in other cells. Furthermore, the accumulation and toxicity of DXR were rescued by CLDN1 siRNA in A549R cells. We suggest that CLDN1 is upregulated by CDDP resistance through activation of a PI3K/Akt/NF-κB pathway, resulting in the inhibition of penetration of anticancer drugs into the inner area of spheroids.
Volume 1865(5)
Pages 769-780
Published 2018-5-1
DOI 10.1016/j.bbamcr.2018.03.001
PII S0167-4889(18)30036-3
PMID 29524521
MeSH A549 Cells Adenocarcinoma / drug therapy* Adenocarcinoma / genetics Adenocarcinoma / pathology Adenocarcinoma of Lung Cell Membrane Permeability / drug effects Cell Proliferation / drug effects Cisplatin / administration & dosage Claudin-1 / genetics* Doxorubicin / administration & dosage* Doxorubicin / adverse effects Drug Resistance, Neoplasm / genetics* Gene Expression Regulation, Neoplastic / drug effects Humans Lung Neoplasms / drug therapy* Lung Neoplasms / genetics Lung Neoplasms / pathology Oncogene Protein v-akt / genetics Phosphatidylinositol 3-Kinases / genetics Protein Serine-Threonine Kinases / genetics RNA, Small Interfering / genetics Signal Transduction Spheroids, Cellular / drug effects
IF 4.739
Times Cited 5
Human and Animal Cells A549