Abstract 3126: Effect of folic acid and docetaxel on the multidrug and folate transporter ABCG2 in prostate cancer

Prostate cancer is the most frequently diagnosed cancer and the second-leading cause of cancer related deaths in American men. It was recently shown that a SNP (Q141K) that decreases the function of the multidrug transporter ABCG2 affects survival outcomes in prostate cancer patients. ABCG2 effluxes mono- and polyglutamated folates and dihydrotestosterone; both are important for prostate growth. We have shown that patients with this SNP have a shorter time to PSA recurrence. Conversely, prostate cancer patients with Q141K and treated with docetaxel had a longer survival time than wild-type patients, supporting our hypothesis that ABCG2 transports docetaxel. Our goal is to determine the role of ABCG2 in prostate carcinogenesis and progression, and if dietary folate can regulate its expression. We observed a decrease of ABCG2 mRNA and protein expression in response to excess levels (2.3µM) of folic acid compared to physiological (25nM) or low (2nM) folic acid in the prostate cancer cell line LNCaP. Because there is a CpG island in the ABCG2 promoter, we hypothesized that ABCG2 expression is regulated by DNA methylation. This hypothesis was supported when we observed that treatment of LNCaP with decitabine, a methylation inhibitor, resulted in significantly increased (p=0.01) ABCG2 mRNA expression. Furthermore, we determined that LNCaP cells grown in low folic acid for 1 week were significantly hypomethylated (p=0.01) at the ABCG2 promoter compared to cells grown in excess folic acid. 5-hmC was recently discovered as a potential intermediate base in the active demethylation process. We found increased 5-hmC in cells grown in low FA relative to those grown in excess FA at one site and no difference at three other sites. To test our hypothesis that ABCG2 can efflux docetaxel we treated LNCaP cells with 1nM docetaxel for 8 days and observed a 5-fold increase in ABCG2 mRNA expression, suggesting a role in docetaxel resistance. In HEK293 cells transduced with ABCG2 or GFP (control) nearly twice as many cells expressing ABCG2 survived docetaxel treatment after 48 hours. In conclusion, we have found that 1) ABCG2 expression is regulated by the availability of folate, via DNA methylation and that 2) ABCG2 may be involved in the transport of docetaxel. Overall, we hypothesize that decreased expression of ABCG2 or the presence of the ABCG2 SNP is associated with disease progression before androgen independence because more folate and DHT could be retained in the cancerous cells thus promoting growth. After androgen independence and docetaxel treatment, ABCG2 expression may increase to efflux docetaxel from the tumor and cause docetaxel resistance. Dietary folate is easily modifiable; therefore the ultimate goal of this study is to determine if we could recommend a dietary component to the treatment regimen for prostate cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3126. doi:1538-7445.AM2012-3126