Insights into the anticancer properties of the first antimicrobial peptide from Archaea

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 9; pp. 2155 - 2164
• Main Authors: Gaglione, Rosa, Pirone, Luciano, Farina, Biancamaria, Fusco, Salvatore, Smaldone, Giovanni, Aulitto, Martina, Dell'Olmo, Eliana, Roscetto, Emanuela, Del Gatto, Annarita, Fattorusso, Roberto, Notomista, Eugenio, Zaccaro, Laura, Arciello, Angela, Pedone, Emilia, Contursi, Patrizia
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2017
• Subjects: Animals; Anticancer peptide; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Antimicrobial peptide; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Archaea; BALB 3T3 Cells; Cell Death - drug effects; Cell Membrane - drug effects; Circular Dichroism; Humans; Mice; Nuclear Magnetic Resonance, Biomolecular; Peptide-membrane interactions; Protein Conformation; Sulfolobus; Sulfolobus - chemistry; Sulfolobus; Peptide-membrane interactions; Archaea; Antimicrobial peptide; Anticancer peptide
• ISSN: 0304-4165; 1872-8006; 1872-8006
• DOI: 10.1016/j.bbagen.2017.06.009

The peptide VLL-28, identified in the sequence of an archaeal protein, the transcription factor Stf76 from Sulfolobus islandicus, was previously identified and characterized as an antimicrobial peptide, possessing a broad-spectrum antibacterial activity. Through a combined approach of NMR and Circular Dichroism spectroscopy, Dynamic Light Scattering, confocal microscopy and cell viability assays, the interaction of VLL-28 with the membranes of both parental and malignant cell lines has been characterized and peptide mechanism of action has been studied. It is here demonstrated that VLL-28 selectively exerts cytotoxic activity against murine and human tumor cells. By means of structural methodologies, VLL-28 interaction with the membranes has been proven and the binding residues have been identified. Confocal microscopy data show that VLL-28 is internalized only into tumor cells. Finally, it is shown that cell death is mainly caused by a time-dependent activation of apoptotic pathways. VLL-28, deriving from the archaeal kingdom, is here found to be endowed with selective cytotoxic activity towards both murine and human cancer cells and consequently can be classified as an ACP. VLL-28 represents the first ACP identified in an archaeal microorganism, exerting a trans-kingdom activity. [Display omitted] •VLL-28 is the first ACP identified in the archaeal kingdom.•VLL-28 exerts a selective cytotoxic action towards cancer cells.•Residues involved in the interaction between VLL-28 and cell membranes have been identified.•Cell death occurs upon a time-dependent activation of apoptotic cell pathway.