Androgen receptor transcriptional activity and chromatin modifications on the ABCB1/MDR gene are critical for taxol resistance in ovarian cancer cells
| Autor: | Chuck C.-K. Chao, Nian-Kang Sun, Abhidha Kohli, Ting-Chang Chang, Shang-Lang Huang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
ATP Binding Cassette Transporter Subfamily B endocrine system diseases Paclitaxel Transcription Genetic Physiology Clinical Biochemistry Antineoplastic Agents macromolecular substances Chromatin remodeling 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Humans Protein kinase A Protein kinase B PI3K/AKT/mTOR pathway Ovarian Neoplasms Chemistry HEK 293 cells Cell Biology Chromatin Cell biology Androgen receptor Gene Expression Regulation Neoplastic 030104 developmental biology Drug Resistance Neoplasm Receptors Androgen 030220 oncology & carcinogenesis Female Genes MDR Chromatin immunoprecipitation |
| Zdroj: | Journal of cellular physiology. 234(6) |
| ISSN: | 1097-4652 |
| Popis: | We report here that the androgen receptor (AR) and ABCB1 are upregulated in a model of acquired taxol resistance (txr) in ovarian carcinoma cells. AR silencing sensitizes txr cells to taxol threefold, whereas ectopic AR expression in AR-null HEK293 cells induces resistance to taxol by 1.7-fold. AR activation using the agonist dihydrotestosterone (DHT) or sublethal taxol treatment upregulates ABCB1 expression in both txr cells and AR-expressing HEK293 cells. In contrast, AR inactivation using the antagonist bicalutamide downregulates ABCB1 expression and enhances cytotoxicity to taxol. A functional ABCB1 promoter containing five predicted androgen-response elements (AREs) is cloned. Deletion assays reveal a taxol-responsive promoter segment which harbors ARE4. Notably, DHT- or taxol-activated AR potentiates binding of the AR to ARE4 as revealed by the chromatin immunoprecipitation. On the other hand, txr cells display an increase in chromatin remodeling. AR/H3K9ac and AR/H3K14ac complexes bind specifically to ARE4 in response to taxol. Furthermore, acetyltransferase protein levels (p300 and GCN5) are upregulated in txr cells. Silencing of p300 or GCN5 reduces chromatin modification and enhances cytotoxicity in both parental and txr SKOV3 cells. While the phosphatidylinositol 3-kinase (PI3K)/serine/threonine protein kinase (AKT) pathway is significantly activated by taxol, taxol-induced ABCB1 expression, histone posttranslational modifications, and p300 binding to ARE4 are suppressed following inhibition of the PI3K/AKT cellular pathway. These results demonstrate that the AKT/p300/AR axis can be activated to target ABCB1 gene expression in response to taxol, thus revealing a new treatment target to counter taxol resistance. |
| Databáze: | OpenAIRE |
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