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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Authors | Guanyi Zhang, Xichun Liu, Jianzhuo Li, Elisa Ledet, Xavier Alvarez, Yanfeng Qi, Xueqi Fu, Oliver Sartor, Yan Dong, Haitao Zhang |
Journal | Oncotarget
(Oncotarget)
Vol. 6
Issue 27
Pg. 23358-71
(Sep 15 2015)
ISSN: 1949-2553 [Electronic] United States |
PMID | 26160840
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- AR protein, human
- Ligands
- Receptors, Androgen
- Taxoids
- Docetaxel
- cabazitaxel
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Topics |
- Active Transport, Cell Nucleus
- Alternative Splicing
(drug effects)
- Animals
- COS Cells
- Cell Line, Tumor
- Chlorocebus aethiops
- Cytoplasm
(metabolism)
- Docetaxel
- Drug Resistance, Neoplasm
(genetics)
- Fluorescence Recovery After Photobleaching
- Gene Deletion
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Ligands
- Male
- Microtubules
(metabolism)
- Prostatic Neoplasms, Castration-Resistant
(metabolism)
- Protein Structure, Tertiary
- Receptors, Androgen
(genetics, metabolism)
- Signal Transduction
- Taxoids
(chemistry)
- Transcription, Genetic
- Up-Regulation
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