Oncotarget

Research Papers:

Androgen receptor splice variants circumvent AR blockade by microtubule-targeting agents

Guanyi Zhang, Xichun Liu, Jianzhuo Li, Elisa Ledet, Xavier Alvarez, Yanfeng Qi, Xueqi Fu, Oliver Sartor, Yan Dong and Haitao Zhang _

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Oncotarget. 2015; 6:23358-23371. https://doi.org/10.18632/oncotarget.4396

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Abstract

Guanyi Zhang1,2,6, Xichun Liu2,6, Jianzhuo Li1,2,6, Elisa Ledet4,5,6, Xavier Alvarez7, Yanfeng Qi3,6, Xueqi Fu1, Oliver Sartor4,5,6, Yan Dong1,3,6, Haitao Zhang2,6

1College of Life Sciences, Jilin University, Changchun, P.R. China

2Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, USA

3Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, Louisiana, USA

4Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA

5Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, USA

6Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana, USA

7Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA

Correspondence to:

Haitao Zhang, e-mail: [email protected]

Keywords: androgen receptor, splice variants, prostate cancer, taxane chemotherapy, microtubule

Received: April 24, 2015     Accepted: June 09, 2015     Published: June 22, 2015

ABSTRACT

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.


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