Abstract
Abstract The initial growth of most localized prostate cancers (PCa) is slow and dependent on androgens. Thus, early-staged and androgen-dependent cancer is manageable with prostatectomy and primary androgen deprivation therapy by either surgical or medical castration or monotherapy with antiandrogens. However, many prostate cancer patients under primary hormone therapy will relapse and further develop resistance to antiandrogen treatments and progress to a fatal androgen-independent and metastatic stage of which treatment options are limited. Identification of key factors or pathways responsible for the development of androgen-independence and antiandrogen resistance is crucial not only for better understanding of advanced prostate cancer development but also development of novel therapeutic strategies fro this cancer. Based on this background, we have established an antiandrogen-resistant prostate cancer cell line model (LNCaP-BC) by long-term treatment (>6 months) of an androgen-sensitive prostate caner cell line LNCaP with a non-steroidal antiandrogen bicalutamide at various concentrations. Our in vitro growth studies showed that LNCaP-BC cells behaved more malignant and grew aggressively. Compared to LNCaP cells, LNCaP-BC cells grew significantly faster than the untreated LNCaP cells in both normal and androgen-depleted media; were less sensitive to bicalutamide but more sensitive to low level of androgen (R1881); exhibited increased colony formation efficiencies in soft agar assay, enhanced tolerance to hypoxia environment and less sensitive to anticancer drug paclitaxel. Real-time PCR and Western blot results revealed that LNCaP-BC cells exhibited an increased mRNA and protein level of androgen receptor (AR) suggesting that the AR signaling was dysregulated in LNCaP-BC cells. More interestingly, a progressive and persistent up-regulation of an orphan nuclear receptor tailless TLX was observed in LNCaP-BC cells. To determine whether TLX overexpression would be associated with the antiandrogen resistant phenotype in prostate cancer cells, we generated stable-TLX transductants in LNCaP cells, which expressed low endogenous TLX level, by retroviral transduction. The in vitro growth phenotypes of LNCaP-TLX clones were similar to the LNCaP-BC cells, such as less sensitivity to bicalutamide and enhanced growth in charcoal-stripped serum, suggesting that TLX might play a regulatory role in the antiandrogen-resistance in advanced prostate cancer. In summary, we have established a bicalutamide-resistant in vitro model of prostate cancer. Our findings also revealed for the first time that up-regulation of TLX may play a regulatory role in the antiandrogen-resistance development of advanced prostate cancer. 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 4016. doi:10.1158/1538-7445.AM2011-4016
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