Role of the TLR4-androgen receptor axis and genistein in taxol-resistant ovarian cancer cells
| Autor: | Ting-Chang Chang, Chuck C.-K. Chao, Nian-Kang Sun, Shang-Lang Huang |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
endocrine system diseases Paclitaxel Genistein Steroid biosynthesis Biochemistry Small hairpin RNA Transcriptome 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Gene silencing Anticarcinogenic Agents Humans Pharmacology Ovarian Neoplasms Chemistry Gene Expression Profiling Antineoplastic Agents Phytogenic Androgen receptor Gene Expression Regulation Neoplastic Toll-Like Receptor 4 030104 developmental biology Gene Ontology Drug Resistance Neoplasm Receptors Androgen 030220 oncology & carcinogenesis Cancer cell Cancer research Female RNA Interference Chromatin immunoprecipitation Signal Transduction |
| Zdroj: | Biochemical pharmacology. 177 |
| ISSN: | 1873-2968 |
| Popis: | Toll-like receptor 4 (TLR4) is often overexpressed in taxol-resistant cancer cells. Here we used whole-genome transcriptomic analysis to identify 787 upregulated genes in SKOV3 ovarian carcinoma cells that ectopically express TLR4. Using chromatin immunoprecipitation enrichment analysis, we observed that 27.8% of the TLR4-upregulated genes identified were androgen receptor (AR)-regulated genes. Accordingly, AR expression was induced in taxol-resistant SKOV3 cells overexpressing TLR4, whereas depletion of TLR4 by shRNA repressed AR expression. Activation of AR by androgens or silencing of AR using shRNA also regulated expression of AR-related genes. We found that expression of DCDC2, ANKRD18B, ALDH1A1, c14orf105, ITGBL1 and NEB was overexpressed in taxol-resistant cells, suggesting the involvement of these AR-related genes in taxol resistance. Pathway enrichment analysis confirmed that the expression of several upregulated genes enriched in steroid biosynthesis pathways was inducible by androgens, supporting the results of previous studies. We also observed that genistein inhibits AR activation, leading to suppression of AR-driven genes and reduced taxol resistance in ovarian cancer cells. Overall, we identified six TLR4- and AR-regulated genes involved in taxol resistance. Our results reveal that the TLR4/AR axis plays a critical role in taxol resistance and that genistein is a candidate compound to limit chemoresistance and improve cancer treatment in ovarian cancer. |
| Databáze: | OpenAIRE |
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