Abstract 4228: A functional role of OCT4 for prostate tumor initiation

Abstract

Abstract We have established several drug resistant prostate cancer cell lines by long term culturing hormone refractory CWR-R1 cells in medium containing chemotherapeutic drugs. These cells displayed a significant increase in side-population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1. To further characterize drug resistant CWR-R1 prostate cancer cell lines, we performed microarray analysis on two drug resistant cell lines in comparison with the drug sensitive parental line. Our Ingenuity pathway analysis suggested that OCT4/POU5F1, the key transcription factor for regulating pluripotency in embryonic stem cells, was upregulated in the drug-resistant lines compared to the parental cells, which was accompanied with transcriptional activation of a set of OCT4 known target genes. Upregulation of OCT4 in drug resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmed by western blot and specific shRNA knockdown. Analysis of the regulatory region of OCT4 gene revealed that drug-resistant cell lines had reduced methylation compared to the parental line. Furthermore, these drug resistant cells exhibited a significant increase in transformation activity in vitro and tumorigenicity in vivo. Subcutaneous inoculation of as few as ten drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions. Our data suggest that these drug resistant cells may be enriched for tumor initiating cells. Knock-down OCT4 expression in drug-resistant cells by the specific shRNA resulted in a considerable decrease in growth both in vitro and in vivo. Our data suggest that OCT4 may play an essential role in promoting tumor initiation of prostate cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4228.