Lambert Lab

My primary research interest involves studies examining the role of prostate derived factor (PDF) in prostate cancer tumorigenicity. PDF is a divergent member of the transforming growth factor (TGF)-β superfamily and has previously been identified as nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1), macrophage inhibitory cytokine (MIC-1), growth differentiation factor-15 (GDF-15), placental transforming growth factor-β (PTGF-b) and placental bone morphogenetic protein (PLAB). Our laboratory identified PDF as a gene involved in vitamin D-mediated growth inhibition of prostate cancer cells. PDF is highly expressed in human prostate epithelium suggesting a role in prostate homeostasis.

Extensive in vitro studies suggest a role for PDF in tumorigenicity. PDF is up-regulated by vitamin D, NSAIDs, antitumorigenic phytochemicals, peroxisomal proliferator-activated receptor (PPAR)g ligands and other antitumorigenic compounds. PDF is a downstream target of the tumor suppressor genes p53 and EGR-1 and is down-regulated by activation of the protumorigenic PI3K/AKT/GSK-3β pathway, findings that support its role in inhibiting tumor growth.

Although a variety of studies suggest a role of PDF in tumor suppression, these findings are not universal. Indeed, evidence has been presented to support a role for PDF in pancreatic, colorectal and prostatic carcinoma development and progression. Thus, the role of PDF in cancer initiation and progression is not clear at the present time.

Our work focuses on molecular aspects of PDF gene expression and mechanistic studies on PDF function. We have shown the requirement for functional p53 in PDF gene expression in response to vitamin D, cell stress and the antitumorigenic compounds, resveratrol and prodigiosin. Recently, we have made the exciting finding that suppression of JNK signaling induces PDF expression dependent on p53. These studies are particularly intriguing due to the role of JNK in inflammatory signaling and may shed light on the role of PDF as an anti-inflammatory factor in prostate.

Prostatic inflammation is increasingly being recognized as a potential initiating and potentiating factor in the development of prostate cancer. PDF was first cloned in a screen for genes involved in macrophage activation and as a gene induced by NSAIDs in colorectal carcinoma cells. These findings suggested that PDF may have anti-inflammatory potential. We explored this hypothesis by comparing PDF protein expression by immunohistochemistry (IHC) and prostatic inflammation in human prostatectomy samples. We found an inverse correlation between PDF staining intensity and inflammation severity suggestive of a role of PDF in prostatic inflammation. We have extended this finding by examining potential inflammatory pathways that may be influenced by PDF. Interestingly, expression of PDF in PC-3 human prostate cancer cells dramatically inhibits NF-kappa B, a key regulator of pro-inflammatory gene expression. Presently, our working hypothesis that is being explored is that PDF suppresses prostate cancer development and progression by inhibiting inflammation in the prostate.

We have broadened our approach to studying PDF action by moving into animal models of prostate cancer. We are performing studies to determine the tumor suppressive capacity of PDF in the PTEN mouse model of prostate cancer development. Prostatic deletion of PTEN results in prostate cancer development with kinetics that recapitulates the human disease. We are crossing mice with ubiquitous expression of PDF (PDF transgenic) with the PTEN knock out animals and will examine the effect of PDF on prostate cancer development in this model system. We propose that PDF will suppress prostate cancer development in this model. If this result is achieved, it will open up a wide variety of new areas of research and potential funding opportunities for our studies on PDF in prostate cancer.

Finally, we have made the striking observation that PDF expression in transgenic mice suppresses the development of prostatic intraepithelial neoplasia, a precursor lesion to prostate cancer. This finding is of potentially very high impact and will serve as the basis for future studies on the tumor suppressive functions of PDF.

Contact

Phone: (303) 724-3472

Fax: (303) 724-3477

E-mail: Jim.Lambert@ucdenver.edu