TLR4 and NFκB signaling is critical for taxol resistance in ovarian carcinoma cells

Autor: Chuck C.-K. Chao, Ting-Chang Chang, Shang-Lang Huang, Nian-Kang Sun
Rok vydání: 2017
Předmět:
0301 basic medicine
ATP Binding Cassette Transporter
Subfamily B
Paclitaxel
endocrine system diseases
Cell Survival
Physiology
Clinical Biochemistry
macromolecular substances
Transfection
Inhibitory Concentration 50
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Gene silencing
Cytotoxic T cell
Promoter Regions
Genetic
Receptor
Ovarian Neoplasms
Sulfonamides
Binding Sites
Dose-Response Relationship
Drug
Chemistry
organic chemicals
Carcinoma
HEK 293 cells
NF-kappa B
Cell Biology
medicine.disease
Antineoplastic Agents
Phytogenic
female genital diseases and pregnancy complications
Up-Regulation
Gene Expression Regulation
Neoplastic
Toll-Like Receptor 4
030104 developmental biology
Drug Resistance
Neoplasm
030220 oncology & carcinogenesis
Cancer research
TLR4
Female
RNA Interference
Ectopic expression
Ovarian cancer
Signal Transduction
Zdroj: Journal of Cellular Physiology. 233:2489-2501
ISSN: 0021-9541
DOI: 10.1002/jcp.26125
Popis: We report here that toll-like receptor 4 (TLR4) and ABCB1 are upregulated in SKOV3 ovarian carcinoma cells that acquired resistance to the anticancer drug taxol. Silencing of TLR4 using short-hairpin RNA sensitized taxol-resistant SKOV3 cells to taxol (4.6 fold), whereas ectopic expression of TLR4 in parental, taxol-sensitive SKOV3 cells or TLR4-null HEK293 cells induced taxol resistance (∼2 fold). A sub-lethal dose of taxol induced ABCB1 protein expression in taxol-resistant SKOV3 cells. Inactivation of TLR4 using chemical inhibitors (CLI-095 and AO-I) downregulated ABCB1 protein expression and enhanced the cytotoxic activity of taxol in taxol-resistant SKOV3 cells. While the sensitization effect of TLR4 inactivation was also detected in TOV21G ovarian cancer cells, which express moderate level of TLR4, ectopic expression of ABCB1 prevented the sensitization effect in these cells. Notably, the NFκB pathway was significantly activated by taxol, and inhibition of this pathway suppressed TLR4-regulated ABCB1 expression. Furthermore, taxol-induced NFκB signaling was reduced following TLR4 silencing in taxol-resistant SKOV3 cells. Consistent with these results, ectopic expression of TLR4 in taxol-sensitive SKOV3 cells enhanced ABCB1 expression and conferred resistance to taxol. The protective effect of exogenous TLR4 expression against taxol was reduced by treatment with NFκB inhibitor in these cells. These results demonstrate that taxol activates the TLR4-NFκB pathway which in turn induces ABCB1 gene expression. This cellular pathway thus represents a novel target to limit resistance to taxol in ovarian cancer cells.
Databáze: OpenAIRE
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