PE and PS Lipids Synergistically Enhance Membrane Poration by a Peptide with Anticancer Properties

Autor(es)

Leite, Natalia Bueno ^[1] ; Aufderhorst-Roberts, Anders ^{[2, 3]} ; Palma, Mario Sergio ^{[4, 5, 6]} ; Connell, Simon D. ^{[2, 3]} ; Ruggiero Neto, Joao ^[1] ; Beales, Paul A. ^{[7, 3]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista, Sao Paulo State Univ, Dept Phys, Inst Biociencias Letras & Ciencias Exatas, Sao Paulo - Brazil

^[2] Univ Leeds, Sch Phys & Astron, Leeds, W Yorkshire - England

^[3] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds, W Yorkshire - England

^[4] Univ Estadual Paulista, Sao Paulo State Univ, Ctr Studies Social Insects, Sao Paulo - Brazil

^[5] Univ Estadual Paulista, Sao Paulo State Univ, Dept Biol, Sao Paulo - Brazil

^[6] Univ Estadual Paulista, Sao Paulo State Univ, Inst Biociencias, Sao Paulo - Brazil

^[7] Univ Leeds, Sch Chem, Leeds LS2 9JT, W Yorkshire - England

• Tipo de documento: Artigo Científico
• Fonte: BIOPHYSICAL JOURNAL; v. 109, n. 5, p. 936-947, SEP 1 2015.
• Citações Web of Science: 40

Resumo

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. (AU)

• Processo FAPESP: 11/11640-5 - Interação de peptídeos líticos e membranas modelo: ação interfacial e indução de domínios lipídicos
• Beneficiário: João Ruggiero Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 11/51684-1 - Biologia de sistemas como estratégia experimental para a descoberta de novos produtos naturais na fauna de artrópodes peçonhentos do Estado de São Paulo
• Beneficiário: Mario Sergio Palma
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Temático