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

Cancers

Yuan-Chang Dai¹  Wei-Min Chung²  Wen-Lung Ma²  Wei-Chun Chang²  Yao-Ching Hung²  Yen-Ping Ho³  Lumin Chen³ 

[1] Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi City 60002, Taiwan;Graduate Institution of Clinical Medical Science, and Graduate Institute of BioMedical Sciences, School of Medicine, China Medical University, Taichung 40403, Taiwan;Sex Hormone Research Center, Department of Obstetrics and Gynecology, and Reproductive Medicine Center, China Medical University Hospital, Taichung 40403, Taiwan;

关键词: ovarian cancer serous subtype;    androgen receptor;    ABCG2;    aryl hydrocarbon receptor;    paclitaxel resistance;   

DOI  :  10.3390/cancers11040463

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown