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Daniel Djakiew

Title

Professor

Department

Biochemistry and Molecular and Cellular Biology
General profile

Phone

+1 202-687-1203

Fax

202-687-1823

Location

Med-Dent

Bio

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. We have identified the p75 neurotrophin receptor (p75NTR), a receptor for nerve growth factor, as a tumor suppressor protein in the prostate. The p75NTR 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 p75NTR with progression of cancer. However, the gene for p75NTR 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 p75NTR 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 small molecules with efficacy as anti-cancer agents by induction of the p75NTR as a new drugable target for prostate cancer therapy. We have demonstrated that the aryl propionic acid class of NSAIDs exhibit differential efficacy for induction of the p75NTR in prostate cancer cells independent of cyclo-oxygenase inhibition. The aryl propionic acid class of NSAIDs induce p75NTR mRNA stability leading to p75NTR 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. Significantly, the same NSAIDs that induce p75NTR expression also induce NSAID activated gene-1 (Nag-1) protein, a divergent member of the transforming growth factor beta (TGF-?) family that is expressed downstream of p75NTR. Moreover, NSAID induced Nag-1 expression selectively mediates cell migration associated with metastasis suppressor activity, whereas p75NTR expression exhibits apoptotic tumor suppressor activity. We are actively investigating additional classes of compounds that can stimulate p75NTR expression levels so as to form a basis upon which more potent compounds can be modified and designed as investigational drugs for inhibition of prostate cancer.

Opposite to the action of NSAIDs to induce p75NTR and Nag-1 we have also identified selected phytoestrogens that inhibit NSAID induced p75NTR levels via the same p38 MAPK pathway. Since elevated levels of p75NTR inhibit neuronal cell survival, inhibition of p75NTR may promote neuronal cell survival following trauma, disease or chemically induced neurotoxicity. Hence, we are actively investigating additional classes of compounds that can inhibit p75NTR expression that can be modified and designed as investigational drugs for the promotion of neuronal cell survival.

Education

  • Research Fellow (1985) Georgetown University, Reproductive Biology
  • PhD (1984) University of Newcastle, Australia, Reproductive Biology
  • B.SC.(HON1) (1978) University of Newcastle, Australia, Biology