臺灣博碩士論文加值系統

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 three fold, whereas ectopic AR expression in AR-null HEK293 cells induces resistance to taxol by 1.7 fold. AR activation using the agonist DHT or sub-lethal 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 predictive androgen-response elements (ARE) is cloned. Deletion assays reveal a taxol-responsive promoter segment which harbors an ARE (ARE4). Notably, DHT- or taxol-activated AR potentiates binding of the AR to ARE4 as revealed by chromatin immunoprecipitation (ChIP) assays. On the other hand, txr cells display an increase in chromatin remodelling. 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 relaxation and enhances cytotoxicity in both parental and txr SKOV3 cells. While the PI3K/AKT pathway is significantly activated by taxol, taxol-induced ABCB1 expression, histone post-translational modification and p300 binding to ARE4 are suppressed by the PI3K/AKT inhibitor. We also report mutual transcriptional regulation of Histone H1.0 and Androgen receptor (AR) as a model in driving expression of ABCB1. H1.0 silencing sensitized SKOV3/Tx600 cells to taxol by 2.3 fold and significantly downregulated cryptic transcription factors e.g. AR and c-Myc in response to taxol. On the other hand ectopic expression of H1.0 developed resistance to taxol by 8.07 fold and upregulated AR levels in parental SKOV3 cells. Both H1.0 and AR silencing produced similar downregulation effect on ABCB1 while AR inhibitor significantly reduced ABCB1 in cells ectopically expressing H1.0 in response to taxol. H1.0 promoter activity was also induced in the presence of AR expressing plasmid under sublethal taxol dose. Deletion assay revealed ARE1/-2152 and ARE2/-754 sites were taxol-responsive and AR showed potential binding on H1.0 promoter. Moreover PI3K inhibitor significantly reduced H1.0 protein and mRNA levels and sensitized SKOV3/Tx600 cells to taxol and greatly reduced AR binding on H1.0 promoter. Phosphorylation activated AKT levels were also found enhanced in SKOV3/Tx600 cells. The findings suggest that taxol response takes AKT/p300/AR axis to target ABCB1 gene expression and also follow PI3K/AKT pathway to regulate H1.0 via AR to upregulate ABCB1 txr gene.

Table of Contents

Recommendation Letter from the Thesis Advisor…………………………………...
Thesis/Dissertation Oral Defense Committee Certification………………………....
Acknowledgements…………………………………………………………………...iii
Abstract……………………………………………………………………………...v
Table of Contents…………………………………………………………………...vii
List of Figures……………………………………………………………………...x

Chapter 1: Review of Literature………………………………….……………….-1-
1.1 Chemoresistance: a limitation to cancer chemotherapy……………................-1-
1.2 Mechanisms behind drug resistance in tumors……………………..................-2-
1.3 Higher relapse rates of ovarian cancer following standard treatments…………………………………………………………..................-3-
1.4 Taxanes induced overexpression of membrane transporters ABCB1…………………………………………………………….................-4-
1.5 Factors affecting gene regulation in drug resistant cancer cells………………-6-
1.6 Epigenetic modifications in ovarian cancer………………………...................-6-
1.7 AR association with ovarian cancer and chemoresistance……………………-7-
1.8 Txr genes and their regulatory factors……………………………...................-9-
1.9 Linker Histone H1.0- chromatin association and transcriptional regulation……………………………………………………………………-11-
Chapter 2: Materials and Methods………………………………………………-14-
2.1 Cell lines and reagents……………………………………………………….-14-
2.2 Plasmids and cell transfection……………………………………………….-15-
2.3 Cell viability assay and taxol resistance…………………………..................-16-
2.4 Quantitative PCR analysis…………………………………………………..-17-
2.5 Western blotting…………………………………………………..................-17-
2.6 Knockdown assay using short-hairpin RNA………………………………...-18-
2.7 Chromatin immunoprecipitation (ChIP) assay………………………………-18-
2.8 Statistical analysis…………………………………………………………...-20-
Chapter 3: Results………………………………………………………………...-21-
3.1 Co-upregulation of AR and ABCB1 in taxol-resistant cells and sensitization to taxol following AR silencing……………………………………………………….-21-
3.2 Identification of taxol-responsive AR element (ARE) of ABCB1 promoter……………………………………………………………………………-23-
3.3 Chromatin epigenetic modifications and potentiated targeting of ABCB1 ARE by taxol treatment…………………………………………………………………..-24-
3.4 Silencing of p300 or GCN5 downregulates ABCB1 expression and sensitizes cells to taxol…………………………………………………...................................-25-
3.5 Silencing of p300 or GCN5 ablates taxol-induced chromatin relaxation and H3K9ac/AR complex targeting to ABCB1 ARE…………………………………...-26-
3.6 PI3K/AKT inhibitor impairs taxol-induced p300 expression, chromatin activation and p300/AR interaction…………………………...................................-27-
3.7 H1.0 knockdown and ectopic expression results in sensitization and resistance to taxol in SKOV3/Tx600 and SKOV3 cells, respectively………………………………………………………………………...-29-
3.8 PI3K is a critical upstream signal of H1.0 expression in cells’ response to taxol………………………………………………………………………………..-30-
3.9 H1.0 silencing downregulates cryptic transcription factors in SKOV3/Tx600 cells under taxol treatment and AR and H1.0 mutually regulate each other to produce similar effect on the downstream txr genes………...................................................-32-
3.10 AR binding on H1.0 promoter enhances H1.0 promoter activity in response to taxol………………………………………………………………………………..-34-
3.11 AR preferentially binds at -2152 ARE1 (AR binding element1) and -754 ARE2 (AR binding element 2) sites on the H1.0 promoter in response to taxol induction in SKOV3 cells……………………………………………………………………….-36-
Figures and Legends……………………………………………………………...-38-
Chapter 4: Discussion…………………………………………………………….-65-
References…………………………………………………………………………-75-

List of Figures

Figure 1: - Upregulation of AR in taxol-resistant cells and sensitization to taxol by genetic silencing of AR……………………………………………………………..-38-
Figure 2: -Identification of taxol-responsive AR element within the ABCB1 promoter……………………………………………………………………………-40-
Figure 3: -Chromatin relaxation and potentiated targeting of ABCB1 ARE by taxol treatment……………………………………………………...................................-42-
Figure 4: -Silencing of p300 or GCN5 downregulates ABCB1 expression and sensitizes cells to taxol………………………………………………………………………...-44-
Figure 5: -Silencing of p300 or GCN5 abrogates taxol-induced chromatin relaxation and H3K9ac/AR complex targeting to ABCB1 ARE…..............................................-46-
Figure 6: -PI3K/AKT inhibitors impair taxol-induced p300 expression, chromatin relaxation and p300/AR interaction………………………………………………..-48-
Figure 7: -Taxol treatment stabilizes p300 protein but this effect is impaired by PI3K/AKT inhibitor………………………………………………………………...-50-
Figure 8: -H1.0 knockdown and ectopic expression results in sensitization and resistance to taxol in SKOV3/Tx600 and SKOV3 cells respectively………………..-52-Figure 9: -PI3K is a critical upstream signal of H1.0 expression in cells’ response to taxol………………………………………………………………………………..-55-
Figure 10: -H1.0 silencing down regulates cryptic transcription factors in SKOV3/Tx600 cells under taxol treatment and AR and H1.0 mutually regulate each other and produce similar effect on ABCB1, a canonical drug resistance gene………………………………………………………………………………...-57-
Figure 11: -AR binding on H1.0 promoter enhances H1.0 promoter activity in response to taxol……………………………………………………………………………...-59-
Figure 12: -AR preferentially binds at -2152 ARE1 (AR binding element1) and -754 ARE2 (AR binding element 2) sites on the H1.0 promoter in response to taxol induction in SKOV3 cells………………………………………...............................................-61-
Figure 13: - Association of the AR or H1.0 protein levels with taxol sensitivity in isogenic SKOV3 txr while these protein levels are revealed insignificant in different ovarian cancer cells ………………………………………………………………..-63-

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