DF/HCC Program Affiliation

Member, Leukemia Program
Member, Cancer Cell Biology Program

Research Abstract

One of the major goals of researchers in the field of apoptosis is understanding the molecular mechanisms of the various components of the apoptotic pathways, with the hope to identify targets for novel cancer therapies. However, most cancer cells are resistant to many apoptosis-inducing agents such as most cytokines and radiation. Tumor necrosis factor has been used in some cancer therapies in an effort to eliminate tumor cells, but its administration results in a severe inflammatory response. Similarly, Fas can kill tumor cells but will also cause a sever hepatotoxicity. Recent discovery of a TNF related ligand, TRAIL, that kills transformed cells with great specificity in vitro, has provided further hope that TRAIL may be used to induce cell death in tumor cells without affecting normal tissue. However, the biological function of TRAIL and what pathways are involved in mediating its function is not yet clear. We are currently studying the biological function and tumor specificity of TRAIL-induced killing by analyzing the effect of TRAIL in inhibiting chronic myelogenous leukemia. Death Receptors (DR) 4 and 5 are activated by TRAIL. The signaling events that mediate the biological effects of TRAIL, DR4 and DR5 are not well characterized. By phage display peptide library screening, we have identified several peptides that directly and specifically interact with DR4 and DR5 receptors. One of the DR5-interacting peptides possesses an inhibitory effect in DR5 and TRAIL-induced cell killing and may provide the mechanism for tumor specificity of TRAIL-induced killing. Identification of pathways that inhibit TRAIL-induced apoptosis in TRAIL-resistant tumor cells will provide valuable targets for cancer therapy. Inhibition of such pathways will convert the TRAIL-resistant tumor cells to TRAIL-sensitive. These cells can then be specifically eliminated by TRAIL-induced apoptosis.

Publications

• Sandra F, Degli Esposti M, Ndebele K, Gona P, Knight D, Rosenquist M, Khosravi-Far R. Tumor necrosis factor-related apoptosis-inducing ligand alters mitochondrial membrane lipids. Cancer Res 2005 Sep 15; 65(18):8286-97
  PMID: 16166305
• Jin TG, Kurakin A, Benhaga N, Abe K, Mohseni M, Sandra F, Song K, Kay BK, Khosravi-Far R. Fas-associated protein with death domain (FADD)-independent recruitment of c-FLIPL to death receptor 5. J Biol Chem 2004 Dec 31; 279(53):55594-601
  PMID: 15485835
• Zhang X, Jin TG, Yang H, DeWolf WC, Khosravi-Far R, Olumi AF. Persistent c-FLIP(L) expression is necessary and sufficient to maintain resistance to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in prostate cancer. Cancer Res 2004 Oct 1; 64(19):7086-91
  PMID: 15466204
• Ghaffari S, Jagani Z, Kitidis C, Lodish HF, Khosravi-Far R. Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor. Proc Natl Acad Sci U S A 2003 May 27; 100(11):6523-8
  PMID: 12750477
• Yang X, Khosravi-Far R, Chang HY, Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell 1997 Jun 27; 89(7):1067-76
  PMID: 9215629
• Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ. Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 1996 Jul; 16(7):3923-33
  PMID: 8668210