The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells
Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and th...
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/5/1094 |
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| author | Jin Xu Xi Yang Dhanraj Deshmukh Hegang Chen Shengyun Fang Yun Qiu |
| author_facet | Jin Xu Xi Yang Dhanraj Deshmukh Hegang Chen Shengyun Fang Yun Qiu |
| author_sort | Jin Xu |
| collection | DOAJ |
| description | Background: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer. |
| first_indexed | 2024-03-10T20:10:24Z |
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| id | doaj.art-56b86b6421344299ab696d8ca5378c0f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:10:24Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-56b86b6421344299ab696d8ca5378c0f2023-11-19T22:58:48ZengMDPI AGCells2073-44092020-04-0195109410.3390/cells9051094The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer CellsJin Xu0Xi Yang1Dhanraj Deshmukh2Hegang Chen3Shengyun Fang4Yun Qiu5Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USAVeterans Affairs Medical Center, Baltimore, MD 21201, USACenter for Biomedical Engineering and Technology, Department of Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USABackground: Drug resistance is one of the most prevalent causes of death in advanced prostate cancer patients. Combination therapies that target cancer cells via different mechanisms to overcome resistance have gained increased attention in recent years. However, the optimal drug combinations and the underlying mechanisms are yet to be fully explored. Aim and methods: The aim of this study is to investigate drug combinations that inhibit the growth of drug-resistant cells and determine the underlying mechanisms of their actions. In addition, we also established cell lines that are resistant to combination treatments and tested new compounds to overcome the phenomenon of double drug-resistance. Results: Our results show that the combination of enzalutamide (ENZ) and docetaxel (DTX) effectively inhibit the growth of prostate cancer cells that are resistant to either drug alone. The downregulation of transcription factor E2F1 plays a crucial role in cellular inhibition in response to the combined therapy. Notably, we found that the androgen receptor (AR) variant AR3 (a.k.a. AR-V7), but not AR full length (AR-FL), positively regulates E2F1 expression in these cells. E2F1 in turn regulates AR3 and forms a positive regulatory feedforward loop. We also established double drug-resistant cell lines that are resistant to ENZ+DTX combination therapy and found that the expression of both AR3 and E2F1 was restored in these cells. Furthermore, we identified that auranofin, an FDA-approved drug for the treatment of rheumatoid arthritis, overcame drug resistance and inhibited the growth of drug-resistant prostate cancer cells both in vitro and in vivo. Conclusion and significance: This proof-of-principle study demonstrates that targeting the E2F1/AR3 feedforward loop via a combination therapy or a multi-targeting drug could circumvent castration resistance in prostate cancer.https://www.mdpi.com/2073-4409/9/5/1094prostate cancercombination therapydrug resistanceandrogen receptor splicing variantsE2F1auranofin |
| spellingShingle | Jin Xu Xi Yang Dhanraj Deshmukh Hegang Chen Shengyun Fang Yun Qiu The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells Cells prostate cancer combination therapy drug resistance androgen receptor splicing variants E2F1 auranofin |
| title | The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells |
| title_full | The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells |
| title_fullStr | The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells |
| title_full_unstemmed | The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells |
| title_short | The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells |
| title_sort | role of crosstalk between ar3 and e2f1 in drug resistance in prostate cancer cells |
| topic | prostate cancer combination therapy drug resistance androgen receptor splicing variants E2F1 auranofin |
| url | https://www.mdpi.com/2073-4409/9/5/1094 |
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