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The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells.
Cells. 2020 Apr 28; 9(5)C

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Veterans Affairs Medical Center, Baltimore, MD 21201, USA. Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Center for Biomedical Engineering and Technology, Department of Physiology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Veterans Affairs Medical Center, Baltimore, MD 21201, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32354165

Citation

Xu, Jin, et al. "The Role of Crosstalk Between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells." Cells, vol. 9, no. 5, 2020.
Xu J, Yang X, Deshmukh D, et al. The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells. Cells. 2020;9(5).
Xu, J., Yang, X., Deshmukh, D., Chen, H., Fang, S., & Qiu, Y. (2020). The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells. Cells, 9(5). https://doi.org/10.3390/cells9051094
Xu J, et al. The Role of Crosstalk Between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells. Cells. 2020 Apr 28;9(5) PubMed PMID: 32354165.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Role of Crosstalk between AR3 and E2F1 in Drug Resistance in Prostate Cancer Cells. AU - Xu,Jin, AU - Yang,Xi, AU - Deshmukh,Dhanraj, AU - Chen,Hegang, AU - Fang,Shengyun, AU - Qiu,Yun, Y1 - 2020/04/28/ PY - 2020/03/20/received PY - 2020/04/17/revised PY - 2020/04/19/accepted PY - 2020/5/2/entrez PY - 2020/5/2/pubmed PY - 2020/5/2/medline KW - E2F1 KW - androgen receptor splicing variants KW - auranofin KW - combination therapy KW - drug resistance KW - prostate cancer JF - Cells JO - Cells VL - 9 IS - 5 N2 - 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. SN - 2073-4409 UR - https://www.unboundmedicine.com/medline/citation/32354165/The_Role_of_Crosstalk_between_AR3_and_E2F1_in_Drug_Resistance_in_Prostate_Cancer_Cells L2 - https://www.mdpi.com/resolver?pii=cells9051094 DB - PRIME DP - Unbound Medicine ER -
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