Abstract 3284: Organ-specific Gst-pi expression in new metastatic androgen-independent prostate cancer animal model

Abstract

Abstract Introduction: Prostate cancer is major leading cause of death in western world. And elucidating the mechanisms of metastasis in prostate cancer, particularly to the bone, is a major issue for treatment of this malignancy. Reactive oxygen species (ROS) have been identified as important chemical mediators in cell growth and differentiation, and glutathione oxidation-reduction (redox) system is the main mechanism against ROS in human body. We established a new metastatic model of prostate cancer, using new cell line, and we investigated the role of glutathione redox system in the androgen-independent prostate cancer. Methods: A new cell line, PCai1, was established from the androgen-independent cancer derived from transgenic rat model for adenocarcinoma of the prostate (TRAP), and investigated its metastatic potential in nude mice. By cDNA microarray analysis in our model, glutathione S-transferase Pi (Gst-pi), which was the major component protein of glutathione redox system, had higher expression in androgen independent prostate cancer. Therefore, effects of Gst-pi knocked down in vitro with iRNA strategy were analyzed in PCai1 cells, and the quantification of ROS was performed by DCFH assay. In addition, to evaluate roles of Gst-pi in castration-resistant cell proliferation, Gst-pi siRNA transfected PCai1 cells were transplanted subcutaneously in castrated or normal nude mice. Results: Gst-pi-siRNA in vitro significantly suppressed cell proliferation rate of PCai1. In addition, high levels of intracellular ROS were recognized in the Gst-pi knockout. Strong expression of Gst-pi was realized castration-resistant prostate cancer specimen, while no tumor was stained in hormone naïve prostate cancer. PCai1 frequently formed metastatic lesions in the lung and lymph nodes after orthotopic implantation in the prostate. Intravenous injections of PCai1, metastasis to lung and bone were obvious. Tumors metastasized in the bone marrow after intravenous injection expressed high levels of Gst-pi, while metastatic lesions in the lung and lymph nodes failed to express Gst-pi as seen in cases of the orthotopic implantation. Knock down of Gst-pi expression of PCai1 significantly inhibited tumor growth of PCai1 compared to negative controls in castrated mice. On the other hand, Gst-pi expression did not affect tumor growth in non-castrated mice Conclusion: Establishment of a new metastatic prostate cancer model allows for the systematic analysis of genetic and molecular characteristics of human tumors. And these results suggest that glutathione redox system can regulate cancer cell growth in androgen free environment. Gst-pi expression of the prostate cancers are dependent on metastatic site, and that Gst-pi has an important role in adapting prostate cancer for growth and metastasis involving an alteration of ROS signals. 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 3284. doi:1538-7445.AM2012-3284