ABSTRACT
Hepatoma-derived growth factor (HDGF) is a heparin-binding growth factor, which has previously been shown to be expressed in a variety of cancers. HDGF overexpression has also previously been correlated with a poor prognosis in several cancers. The significance of HDGF in prostate cancer, however, has not been investigated. Here, we show that HDGF is overexpressed in both androgen-sensitive LNCaP cells and androgen-insensitive DU145, 22RV1, and PC-3 cells. Forced overexpression enhanced cell viability of RWPE-1 cells, whereas HDGF knockdown reduced cell proliferation in human prostate cancer cells. We also show that HDGF may serve as a survival-related protein as ectopic overexpression of HDGF in RWPE cells up-regulated the expression of antiapoptosis proteins cyclin E and BCL-2, whereas simultaneously down-regulating proapoptotic protein BAX. Western blot analysis also showed that HDGF overexpression modulated the activity of phospho-AKT as well as NF-kB, and these results correlated with in vitro migration and invasion assays. We next assessed the therapeutic potential of HDGF inhibition with a HDGF monoclonal antibody and vitamin k2, showing reduced cell proliferation as well as inhibition of NF-kB expression in HDGF overexpressed RWPE cells treated with a HDGF monoclonal antibody and vitamin K2. Collectively, our results suggest that HDGF is a relevant protein in prostate oncogenesis and may serve as a potential therapeutic target in prostate cancer.
Subject(s)
Adenocarcinoma/pathology , Intercellular Signaling Peptides and Proteins/physiology , Prostatic Neoplasms/pathology , Adenocarcinoma/metabolism , Androgens , Antibodies, Monoclonal/pharmacology , Apoptosis/drug effects , Cell Division/drug effects , Cell Line, Tumor , Cell Survival , Cell Transformation, Neoplastic , Drug Screening Assays, Antitumor , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/pharmacology , Male , Molecular Targeted Therapy , NF-kappa B/metabolism , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Neoplasms, Hormone-Dependent/metabolism , Neoplasms, Hormone-Dependent/pathology , Prostate/cytology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms, Castration-Resistant/metabolism , Prostatic Neoplasms, Castration-Resistant/pathology , RNA Interference , RNA, Small Interfering/pharmacology , Recombinant Proteins/metabolism , Vitamin K 2/pharmacologyABSTRACT
High-mobility group box 1 (HMGB1) is a dynamic nuclear protein participating in transcription, chromatin remodelling, and DNA recombination and repair processes. Accumulating evidence indicates that its function now extends beyond the nucleus, notably its extracellular role in inflammation. HMGB1 is implicated as a late mediator of sepsis and is also believed to promote atherosclerosis and other inflammatory diseases such as rheumatoid arthritis and systemic lupus erythematosus. Interestingly, deregulation of HMGB1 is shown to be associated with the hallmarks of cancer development. Moreover, several clinical studies have shown that HMGB1 is a promising biomarker for a variety of cancer types. In this review, we provide novel insights into the role and mechanisms of HMGB1, in particular, to hormone-related cancers and its potential to serve as a therapeutic target.
