EXPRESSION OF AN ONCOGENIC TRANSPORTER, ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3, IMPACTS THE PROGRESSION AND TREATMENT OF PROSTATE CANCER
Embargo until
Date
2014-12-10
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
The prostate and prostate cancer requires androgens and androgen receptor signaling to grow. Previous dogma dictated that androgens passively diffuse through the plasma membrane. Our laboratory was the first to demonstrate that organic anion polypeptide 1B3 (OATP1B3) facilitated the uptake of testosterone into cells. This finding was contradictory to prior beliefs that testosterone merely diffuses into cells. Moreover, variability in OATP1B3 function was related to a 2-year survival difference in patients and a decrease in the progression-free survival after androgen deprivation therapy (ADT). We hypothesize that OATP1B3 expression is a hallmark of early prostate cancer that confers a significant growth advantage by facilitating the influx of androgens, especially in a hypoxic and low-androgen environment. However, little is known about the mechanism underlying OATP1B3 expression in cancer and the impact of OATP1B3 transport on tumor growth. Therefore, we completed a study investigating expression levels of OATPs in cancer, assessing hypoxia-induced expression of OATP1B3, characterizing the impact of OATP1B3-mediated androgen transport on prostate cancer, and examining whether transport by OATP1B3 impacts antiandrogen or chemotherapy treatments. First, we showed that of OATP1B1, OATP1B3, and OATP2B1 only OATP1B3 was de novo expressed in prostate cancer samples from patients. Second, we found that OATP1B3 co-localized with hypoxia inducible factor-1 alpha (HIF-1) in prostate cancer tissues from patients and expression in a cell-line was induced under hypoxic conditions. Third, we then showed that OATP1B3 transported testosterone and dihydrotestosterone (DHT) over passive diffusion alone in radioactive transport assays with Xenopus laevis oocytes. A prostate cancer cell line overexpressing OATP1B3 grew more than non-expressing cells in response to androgens at low androgen concentrations. Finally, OATP1B3 decreased cell sensitivity to an antiandrogen, bicalutamide, and increased cell sensitivity to a chemotherapy treatment, docetaxel. In summary, these data showed that hypoxia increased OATP1B3 expression in prostate cancer, OATP1B3-mediated androgen transport increased prostate cancer growth, and transport by OATP1B3 in tumors may explain the efficacy of certain therapeutics in prostate cancer. Given the potential importance of OATP1B3 in prostate cancer, future studies will; establish the physiological importance of androgen transport in knockout mice, screen for OATP1B3 inhibitors to possibly improve prostate cancer treatment outcomes, image patients with prostate cancer lesions using OATP1B3-specific probes, and investigate OATP1B3 transport as a novel therapeutic resistance mechanism.
Description
Keywords
Organic Anion Polypeptide 1B3, testosterone transport, prostate cancer transporter