title: killerFLIP: a novel lytic peptide specifically inducing cancer cell death.
abstract: One of the objectives in the development of effective cancer therapy is induction of tumor-selective cell death. Toward this end, we have identified a small peptide that, when introduced into cells via a TAT cell-delivery system, shows a remarkably potent cytoxicity in a variety of cancer cell lines and inhibits tumor growth in vivo, whereas sparing normal cells and tissues. This fusion peptide was named killerFLIP as its sequence was derived from the C-terminal domain of c-FLIP, an anti-apoptotic protein. Using structure activity analysis, we determined the minimal bioactive core of killerFLIP, namely killerFLIP-E. Structural analysis of cells using electron microscopy demonstrated that killerFLIP-E triggers cell death accompanied by rapid (within minutes) plasma membrane permeabilization. Studies of the structure of the active core of killerFLIP (-E) indicated that it possesses amphiphilic properties and self-assembles into micellar structures in aqueous solution. The biochemical properties of killerFLIP are comparable to those of cationic lytic peptides, which participate in defense against pathogens and have also demonstrated anticancer properties. We show that the pro-cell death effects of killerFLIP are independent of its sequence similarity with c-FLIPL as killerFLIP-induced cell death was largely apoptosis and necroptosis independent. A killerFLIP-E variant containing a scrambled c-FLIPL motif indeed induced similar cell death, suggesting the importance of the c-FLIPL residues but not of their sequence. Thus, we report the discovery of a promising synthetic peptide with novel anticancer activity in vitro and in vivo.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Pennarun
authors.forename: G
authors.initials: G
authors.lastname: Gaidos
authors.forename: O
authors.initials: O
authors.lastname: Bucur
authors.forename: A
authors.initials: A
authors.lastname: Tinari
authors.forename: C
authors.initials: C
authors.lastname: Rupasinghe
authors.forename: T
authors.initials: T
authors.lastname: Jin
authors.forename: R
authors.initials: R
authors.lastname: Dewar
authors.forename: K
authors.initials: K
authors.lastname: Song
authors.forename: M T
authors.initials: MT
authors.lastname: Santos
authors.forename: W
authors.initials: W
authors.lastname: Malorni
authors.forename: D
authors.initials: D
authors.lastname: Mierke
authors.forename: R
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D008854:Microscopy, Electron; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides