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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Autores principales: Xu, Jin, Yang, Xi, Deshmukh, Dhanraj, Chen, Hegang, Fang, Shengyun, Qiu, Yun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290672/
https://www.ncbi.nlm.nih.gov/pubmed/32354165
http://dx.doi.org/10.3390/cells9051094
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author Xu, Jin
Yang, Xi
Deshmukh, Dhanraj
Chen, Hegang
Fang, Shengyun
Qiu, Yun
author_facet Xu, Jin
Yang, Xi
Deshmukh, Dhanraj
Chen, Hegang
Fang, Shengyun
Qiu, Yun
author_sort Xu, Jin
collection PubMed
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.
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spelling pubmed-72906722020-06-17 The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells Xu, Jin Yang, Xi Deshmukh, Dhanraj Chen, Hegang Fang, Shengyun Qiu, Yun Cells Article 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. MDPI 2020-04-28 /pmc/articles/PMC7290672/ /pubmed/32354165 http://dx.doi.org/10.3390/cells9051094 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Jin
Yang, Xi
Deshmukh, Dhanraj
Chen, Hegang
Fang, Shengyun
Qiu, Yun
The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290672/
https://www.ncbi.nlm.nih.gov/pubmed/32354165
http://dx.doi.org/10.3390/cells9051094
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