title: Taxane-induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer.
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 β-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.
authors.affiliation: Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College of Cornell University, New York, New York 10065-4896, USA.
authors.forename: Medha S
authors.initials: MS
authors.lastname: Darshan
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Loftus
authors.forename: Maria
authors.initials: M
authors.lastname: Thadani-Mulero
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Levy
authors.forename: Daniel
authors.initials: D
authors.lastname: Escuin
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.forename: Ada
authors.initials: A
authors.lastname: Gjyrezi
authors.forename: Chantal
authors.initials: C
authors.lastname: Chanel-Vos
authors.forename: Ruoqian
authors.initials: R
authors.lastname: Shen
authors.forename: Scott T
authors.initials: ST
authors.lastname: Tagawa
authors.forename: Neil H
authors.initials: NH
authors.lastname: Bander
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004398:Dyneins / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001952:Bridged-Ring Compounds; D011944:Receptors, Androgen; D043823:Taxoids; C080625:taxane; D004398:Dyneins