Research Interest

Prostate cancer is the most commonly diagnosed cancer and ranks as the second leading cause of cancer related deaths among men in the United States. Recent epidemiological studies found a correlation between long term NSAID (non-steroidal anti-inflammatory drug) use and decreased prostate cancer risk. In addition, many in vitro studies involving various human prostate cancer cell lines consistently demonstrate decreased proliferation and increased apoptosis in response to selected NSAID treatment. NSAIDs represent a diverse group of compounds often with unrelated chemical structures. Most NSAIDs exhibit anti-inflammatory, anti-pyretic and analgesic activities through inhibition of the cyclo-oxygenase enzymes. In addition, some, but not all NSAIDs exhibit anti-cancer activity at higher concentrations of drug. Moreover, some derivatives of NSAIDs, such as R-flurbiprofen and sulindac sulfone, have no cyclo-oxygenase inhibitory activity, and still exhibit anticancer activity. In this context, we recently identified the p75^NTR tumor suppressor as a drugable target for NSAID inhibition of prostate cancer growth independent of cyclo-oxygenase inhibition. The p75^NTR is a member of the tumor necrosis factor receptor super-family of membrane receptors which shares an intracellular sequence of amino acids called the death domain that can induce apoptosis. Normal prostate epithelial cells loose expression of the p75^NTR with progression of cancer. However, the gene in these cells remains intact, so that the possibility remains for re-expression of protein. Our team is one of the very few research laboratories to investigate the role of the p75^NTR tumor suppressor in prostate cancer. Our research lead to a major discovery of this novel mechanism of prostate cancer progression, and concomitantly, has lead to the discovery of a new class of small molecules with efficacy as anti-cancer agents by induction of the p75^NTR as a new drugable target for prostate cancer therapy. Our early observations demonstrated that the aryl propionic acid class of NSAIDs exhibited differential efficacy for induction of the p75^NTR in prostate cancer cells independent of cyclo-oxygenase inhibition. The aryl propionic acids induce p75^NTR mRNA stability leading to p75^NTR dependent apoptosis of tumor cells. The mechanism of action for this enhanced mRNA stability occurs via aryl propionic acid mediated phosphorylation of the p38 MAPK. We are actively investigating additional classes of compounds that can stimulate p75^NTR expression levels so as to form a basis upon which more potent compounds can be modified and designed as investigation drugs for inhibition of prostate cancer.

Selected Publications

E. QUANN, F KHWAJA, D. DJAKIEW (2007). The p38 MAPK Pathway Mediates Aryl Propionic Acid Induced messenger RNA Stability of p75^NTR in Prostate Cancer Cells. Cancer Research 67, 11402-11410.

E. QUANN, F KHWAJA, K H. ZAVITZ, D. DJAKIEW (2007). The Aryl Propionic Acid R-Flurbiprofen Selectively Induces p75^NTR-Dependent Decreased Survival of Prostate Tumor Cells. Cancer Research 67, 3254-62.

A NALBANDIAN, D. DJAKIEW (2006). The p75^NTR metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells. Clinical and Experimental Metastasis 23, 107-116.

F. KHWAJA, A. TABASSUM, J. ALLEN, D. DJAKIEW (2006). The p75^NTR tumor suppressor induces cell cycle arrest facilitating caspase mediated apoptosis in prostate tumor cells. Biochemical and Biophysical Research Communications 341, 1184-1192.

D. DJAKIEW (2006) Cancer of the Prostate – Mechanisms of Molecular Carcinogenesis. In “Molecular Carcinogenesis and the Molecular Biology of Human Cancer” Eds D. Warshawsky & J. Landolph, CRC Press LLC, p363-377.

A NALBANDIAN, A.L. PANG, O.M. RENNART, W.-Y. CHAN, N. RAVINDRANATH, D. DJAKIEW (2005). A novel function of differentiation revealed by cDNA microarray profiling of p75^NTR-regulated gene expression. Differentiation 73, 385-396.

J. ALLEN, F. KHWAJA, S. BYERS, D. DJAKIEW (2005). The p75^NTR Mediates a Bifurcated Signal Transduction Cascade through the NFκB and JNK Pathways to Inhibit Cell Survival. Experimental Cell Research 304, 69-80.

D. G. BOSTWICK, H. B. BURKE, D. DJAKIEW, S. EULING, S.-M. HO, J. LANDOLPH, H. MORRISON, B. SONAWANE, T. SHIFFLETT, D. WATERS, B. TIMMS (2004) Human Prostate Cancer Risk Factors. Cancer 101 (Supplement 10), 2371-490.

J. ALLEN, F. KHWAJA, D. DJAKIEW (2004). Gene Therapy of Prostate Xenograft Tumors with a p75^NTR Lipoplex. Anticancer Research 24, 2997-3003.