PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties.
Polybia-MP1 (MP1) is a bioactive host-defense peptide with known anticancer properties. Its activity is attributed to excess serine (phosphatidylserine (PS)) on the outer leaflet of cancer cells. Recently, higher quantities of phosphatidylethanolamine (PE) were also found at these cells' surface. We investigate the interaction of MP1 with model membranes in the presence and absence of POPS (PS) and DOPE (PE) to understand the role of lipid composition in MP1's anticancer characteristics. Indeed we find that PS lipids significantly enhance the bound concentration of peptide on the membrane by a factor of 7-8. However, through a combination of membrane permeability assays and imaging techniques we find that PE significantly increases the susceptibility of the membrane to disruption by these peptides and causes an order-of-magnitude increase in membrane permeability by facilitating the formation of larger transmembrane pores. Significantly, atomic-force microscopy imaging reveals differences in the pore formation mechanism with and without the presence of PE. Therefore, PS and PE lipids synergistically combine to enhance membrane poration by MP1, implying that the combined enrichment of both these lipids in the outer leaflet of cancer cells is highly significant for MP1's anticancer action. These mechanistic insights could aid development of novel chemotherapeutics that target pathological changes in the lipid composition of cancerous cells.
Department of Physics, Instituto de Biociências Letras e Ciências Exatas, São Paulo State University, Universidade Estadual Paulista "Júlio de Mesquita Filho", São Paulo, Brazil.
Natália Bueno
NB
Leite
School of Physics and Astronomy and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
Anders
A
Aufderhorst-Roberts
Center of Studies of Social Insects and Department of Biology and Instituto de Biociências, São Paulo State University, Universidade Estadual Paulista "Júlio de Mesquita Filho", São Paulo, Brazil.
Mario Sergio
MS
Palma
School of Physics and Astronomy and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK.
Simon D
SD
Connell
Department of Physics, Instituto de Biociências Letras e Ciências Exatas, São Paulo State University, Universidade Estadual Paulista "Júlio de Mesquita Filho", São Paulo, Brazil. Electronic address: jruggiero@sjrp.unesp.br.
João
J
Ruggiero Neto
School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK. Electronic address: p.a.beales@leeds.ac.uk.
Paul A
PA
Beales
D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D010718:Phosphatidylserines / Q000378:metabolism*; D016062:Porosity / Q000187:drug effects; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism; D014862:Wasp Venoms / Q000494:pharmacology*
D023181:Antimicrobial Cationic Peptides; D000970:Antineoplastic Agents; D010714:Phosphatidylethanolamines; D010718:Phosphatidylserines; D053835:Unilamellar Liposomes; D014862:Wasp Venoms; C582416:polybia-MPI, Polybia paulista; C483858:phosphatidylethanolamine