Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer

Medha S. Darshan, Matthew S. Loftus, Maria Thadani-Mulero, Benjamin P. Levy, Daniel Escuin, Xi Kathy Zhou, Ada Gjyrezi, Chantal Chanel-Vos, Ruoqian Shen, Scott T. Tagawa, Neil H. Bander, David M. Nanus, Paraskevi Giannakakou

Research output: Contribution to journalArticle

Abstract

Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that taxanes can also affect AR signaling. Here, we report that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired b-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy.

Original languageEnglish (US)
Pages (from-to)6019-6029
Number of pages11
JournalCancer Research
Volume71
Issue number18
DOIs
StatePublished - Sep 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer'. Together they form a unique fingerprint.

  • Cite this

    Darshan, M. S., Loftus, M. S., Thadani-Mulero, M., Levy, B. P., Escuin, D., Zhou, X. K., Gjyrezi, A., Chanel-Vos, C., Shen, R., Tagawa, S. T., Bander, N. H., Nanus, D. M., & Giannakakou, P. (2011). Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer. Cancer Research, 71(18), 6019-6029. https://doi.org/10.1158/0008-5472.CAN-11-1417