The peptide derived from the Ig-like domain of human herpesvirus 8 K1 protein induces death in hematological cancer cells

Background: although significant progress has been made in the treatment of lymphomas,many lymphomas exhibit resistance to cell death,suggesting a defective fas signaling,which remains poorly understood. we previously reported that cells expressing the k1 protein of human herpesvirus 8 (hhv-8) resist death through the complex formation of the ig-like domain of k1 with fas. recently,we investigated whether peptides derived from the ig-like domain of the k1 protein may affect cell death. methods: k1 positive and negative cell lines were incubated with the k1-derived peptides,and cell death (apoptotic and necrotic) was assessed by flow cytometry and ldh assay. activation of caspases was assessed by fluorometric assay and flow cytometry. fas receptor-independent,peptide-mediated cell killing was tested in the fas-resistant daudi cell line and jurkat cell clones deficient in caspase-8 and fadd functionality. activation of tnf receptors i and ii was blocked by pre-incubation with corresponding blocking antibodies. the effect of the k1 peptide in vivo was tested in a mouse xenograft model. results: we observed that the peptide s20-3 enhanced cell death in k1-positive bjab cells and hhv-8 positive primary effusion lymphoma (pel) cell lines. similar effects of this peptide were observed in b-cell lymphoma and t-lymphoblastic leukemia cells without k1 expression but not in normal human peripheral blood mononuclear cells. a single intratumoral injection of the s20-3 peptide decreased the growth of jurkat xenografts in scid mice. the mechanism of tumor cell death induced by the s20-3 peptide was associated with activation of caspases,but this activity was only partially inhibited by the pan-caspase inhibitor z-vad. furthermore,the k1 peptide also killed fas-resistant daudi cells,and this killing effect was inhibited by pre-incubation of cells with antibodies blocking tnfri. conclusion: taken together,these findings indicate that the s20-3 peptide can selectively induce the death of malignant hematological cell lines by fas- and/or tnfri-dependent mechanisms,suggesting the k1-derived peptide or peptidomimetic may have promising therapeutic potential for the treatment of hematological cancers. © 2012 daniluk et al.; licensee biomed central ltd.