Prostate cancer is the most common cancer among older men and the second leading cancer-related cause of death in them. It is responsible for nearly 30,000 deaths per year in the United States. The causes for the development of prostate cancer are not clearly known although age and genetic factors play a key role in the etiology of this cancer. Epidemiological and experimental studies suggest that deregulated androgen levels and chronic inflammation also predispose to prostate cancer. However, the underlying molecular mechanisms which result in prostate cancer are not yet well known. Therefore, this study focuses on characterizing the role of High Mobility Group Box 1 protein (HMGB1), a co-activator of sex hormone receptors and a pro-inflammatory cytokine in the development of prostate carcinogenesis. In this study, we used an immortalized normal prostate cell (RWPE-1) to test if expression of HMGB1 in these cells will activate oncogenic signaling and transform them to a malignant phenotype. To achieve this, RWPE-1 cells were transfected with HMGB1 gene; stable lines were constructed and designated as RWPE-HMGB1. Cell cycle analysis by flow cytometry showed that majority (73%) of RWPE-1 cells over expressing HMGB1 was in the G2/M phase followed by polyploidy state (25%). Importantly, RWPE-HMGB1 cells when exposed to R1881 (synthetic androgen) treatment proliferated significantly in a time dependent manner compared to control RWPE-1 cells. Interestingly, the proliferative effects of HMGB1 in RWPE-1 cells was inhibited by anti-androgenic treatment (casodex) implicating HMGB1 to be a co-activator of androgen receptor in prostate cells. Further mechanistic studies revealed that expression of HMGB1 in RWPE-1 cells stimulated androgen receptor expression and PSA secretion in these cells. In addition, our studies also identified HMGB1 as an activator of two key extracellular (Extracellular signal-regulated kinase [Erk] and Toll-like receptor-4 [TLR-4]) pathways in RWPE-1 cells resulting in the inhibition of caspase-3 activation and prevention of PARP-1 cleavage suggesting HMGB1 is an inhibitor of apoptosis in prostate cancer cells. Overall, results of our study have identified a potential role of HMGB1 in prostate cancer which may help design drugs to target HMGB1 in preventing prostate carcinogenesis.

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 535. doi:1538-7445.AM2012-535

©2012 American Association for Cancer Research
2012