Abstract 4006: Orphan nuclear receptor tailless TLX performs an oncogenic function in prostate cancer cells via its promotion of androgen-independent growth and induction of epithelial – mesenchymal transition phenotype

Abstract

Abstract The Tailless TLX gene (NR2E1), which was initially identified as a vertebrate homolog to the Drosophila terminal-gap gene tailless (tll), is an orphan nuclear receptor and functions mainly as a constitutive transcriptional repressor. Functional studies show that TLX plays important roles in the maintenance and self-renewal of both embryonic and adult neural stem cells. Transgenic mice with TLX overexpression show that in vivo ectopic TLX expression can lead to uncontrolled expansion of a subgroup of neural stem cells and cause initiation of glioma. In a preliminary screening of expression patterns of nuclear receptors in prostatic cell lines and clinical prostate cancer tissues, we identified that TLX transcripts were significantly overexpressed in many prostate cancer cell lines. Furthermore, by immunohistochemistry, increased TLX nuclear immunosignals were detected in high Gleason-scored (≥4) and also hormone-refractory (castration- and flutamide- resistant) prostate cancer, paired neoplastic human prostatic tissues, suggesting that TLX up-regulation may be positively associated with the advanced progression of prostate cancer. Based on these observations, we hypothesize that TLX may play growth regulatory roles in prostate cancer development. In order to elucidate the functional significance of TLX in prostate cancer growth, we generated stable TLX-infectants in a hormone-sensitive prostate cancer line LNCaP, which expressed low endogenous TLX levels, for growth phenotypic characterization. Our results showed that ectopic TLX expression could enhance the cell proliferation of LNCaP-TLX cells in either normal growth medium or medium with charcoal-stripped fetal bovine serum, accompanied with a decreased p21 expression. The LNCaP-TLX transduced clones, which expressed decreased androgen receptor (AR) and prostatic specific antigen (PSA) expressions, were less sensitive to AR agonist R1881 and antagonist bicalutamide, suggesting that LNCaP-TLX clones were less dependent on androgen but resistant to anti-androgen. Lastly, we also found that LNCaP-TLX infectants become apparently fusiform-shaped and expressed evaluated levels of two epithelial-mesenchymal transition (EMT) markers, Twist and Vimentin, suggesting that an EMT phenotype was induced in LNCaP-TLX cells. Taken together, our results demonstrated for the first time orphan nuclear receptor TLX may play an oncogenic regulatory role in the advanced growth of prostate cancer. (This study was supported by a Direct Grant for Research CUHK, project code 2041534) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4006. doi:10.1158/1538-7445.AM2011-4006