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Cancers 2019, 11(4), 463; https://doi.org/10.3390/cancers11040463

Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

1
Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan
2
Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan
3
Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 60002, Taiwan
4
Department of OBs & GYN, BenQ Medical Center, Suzhou 215004, China
5
Department of Nursing, Asia University, Taichung 41354, Taiwan
*
Authors to whom correspondence should be addressed.
Received: 9 January 2019 / Revised: 11 March 2019 / Accepted: 27 March 2019 / Published: 2 April 2019
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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Abstract

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype. View Full-Text
Keywords: ovarian cancer serous subtype; androgen receptor; ABCG2; aryl hydrocarbon receptor; paclitaxel resistance ovarian cancer serous subtype; androgen receptor; ABCG2; aryl hydrocarbon receptor; paclitaxel resistance
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Chung, W.-M.; Ho, Y.-P.; Chang, W.-C.; Dai, Y.-C.; Chen, L.; Hung, Y.-C.; Ma, W.-L. Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis. Cancers 2019, 11, 463.

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