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

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.
AuthorsGuanyi Zhang, Xichun Liu, Jianzhuo Li, Elisa Ledet, Xavier Alvarez, Yanfeng Qi, Xueqi Fu, Oliver Sartor, Yan Dong, Haitao Zhang
JournalOncotarget (Oncotarget) Vol. 6 Issue 27 Pg. 23358-71 (Sep 15 2015) ISSN: 1949-2553 [Electronic] United States
PMID26160840 (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.)
Chemical References
  • AR protein, human
  • Ligands
  • Receptors, Androgen
  • Taxoids
  • Docetaxel
  • cabazitaxel
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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