Inhibition of the androgen receptor as a novel mechanism of Taxol chemotherapy in prostate cancer

Lu Gan, Shuai Chen, Yuwei Wang, Akira Watahiki, Laura Bohrer, Zhen Sun, Yuzhuo Wang, Haojie Huang

Research output: Contribution to journalArticle

143 Scopus citations

Abstract

Taxol chemotherapy is one of the few therapeutic options for men with castration-resistant prostate cancer (CRPC). However, the working mechanisms for Taxol are not fully understood. Here, we showed that treatment of 22Rv1, a PTEN-positive CRPC cell line, with paclitaxel andits semisynthetic analogue docetaxel decreases expression of the androgen receptor (AR)-activatedgen es prostate-specific antigen (PSA) and Nkx3.1 but increases expression of the AR repression gene maspin, suggesting that Taxol treatment inhibits AR activity. This was further supportedb y the observation that the activity of AR luciferase reporter genes was inhibitedby paclitaxel. In contrast, paclitaxel treatment failedt o inhibit AR activity in the PTEN-null CRPC cell line C4-2. However, pretreatment of C4-2 cells with the phosphoinositide 3-kinase inhibitor LY294002 restoredpa clitaxel inhibition of the AR. Treatment of 22Rv1 xenografts in mice with docetaxel induced mitotic arrest anda decrease in PSA expression in tumor cells adjacent to vascular vessels. We further showedthat paclitaxel induces nuclear accumulation of FOXO1, a known AR suppressive nuclear factor, andincreases the association of FOXO1 with AR proteins in the nucleus. FOXO1 knockdown with small interfering RNA attenuatedthe inhibitory effect of paclitaxel on AR transcriptional activity, expression of PSA andNk x3.1, and cell survival. These data reveal a previously uncharacterized, FOXO1-mediated, AR-inhibitory effect of Taxol in CRPC cells that may play an important role in Taxol-mediated inhibition of CRPC growth.

Original languageEnglish (US)
Pages (from-to)8386-8394
Number of pages9
JournalCancer research
Volume69
Issue number21
DOIs
StatePublished - Nov 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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