RRC ID 58072
著者 Maruhashi R, Eguchi H, Akizuki R, Hamada S, Furuta T, Matsunaga T, Endo S, Ichihara K, Ikari A.
タイトル Chrysin enhances anticancer drug-induced toxicity mediated by the reduction of claudin-1 and 11 expression in a spheroid culture model of lung squamous cell carcinoma cells.
ジャーナル Sci Rep
Abstract The aberrant expression of claudins (CLDNs), which are tight junctional proteins, is seen in various solid tumors, but the regulatory mechanisms and their pathophysiological role are not well understood. Both CLDN1 and CLDN11 were highly expressed in human lung squamous cell carcinoma (SCC). Chrysin, found in high concentration in honey and propolis, decreased CLDN1 and CLDN11 expression in RERF-LC-AI cells derived from human lung SCC. The phosphorylation level of Akt was decreased by chrysin, but those of ERK1/2 and c-Jun were not. LY-294002, an inhibitor of phosphatidylinositol 3-kinase, inhibited the phosphorylation of Akt and decreased the expression levels of CLDN1 and CLDN11. The association between phosphoinositide-dependent kinase 1 (PDK1) and Akt was inhibited by chrysin, but the phosphorylation of PDK1 was not. Immunoprecipitation and quartz-crystal microbalance assays revealed that biotinylated-chrysin binds directly to Akt. The knockdown of CLDN1 and CLDN11 using small interfering RNAs increased the transepithelial flux of doxorubicin (DXR), an anthracycline anticancer drug. Similarly, both chrysin and LY-294002 increased DXR flux. Neither CLDN1 knockdown, CLDN11 knockdown, nor chrysin changed the anticancer drug-induced cytotoxicity in a two-dimensional culture model, whereas they enhanced cytotoxicity in a spheroid culture model. Taken together, chrysin may bind to Akt and inhibit its phosphorylation, resulting in the elevation of anticancer drug-induced toxicity mediated by reductions in CLDN1 and CLDN11 expression in RERF-LC-AI cells. We suggest that chrysin may be useful as an adjuvant chemotherapy in lung SCC.
巻・号 9(1)
ページ 13753
公開日 2019-9-24
DOI 10.1038/s41598-019-50276-z
PII 10.1038/s41598-019-50276-z
PMID 31551535
PMC PMC6760125
MeSH Adenocarcinoma of Lung / drug therapy* Adenocarcinoma of Lung / metabolism Antineoplastic Agents / pharmacology* Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / metabolism Cell Line, Tumor Claudin-1 / genetics* Claudins / genetics* Doxorubicin / pharmacology Flavonoids / pharmacology* Gene Expression Regulation, Neoplastic / drug effects Humans Lung Neoplasms / drug therapy* Lung Neoplasms / metabolism Phosphorylation / drug effects
IF 3.998
引用数 0
リソース情報
ヒト・動物細胞 RERF-LC-AI(RCB0444)