期刊
BIOPHYSICAL JOURNAL
卷 109, 期 5, 页码 936-947出版社
CELL PRESS
DOI: 10.1016/j.bpj.2015.07.033
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资金
- Biomedical & Health Research Centre at the University of Leeds and European Union Marie Curie Career Integration Grant BioNanoMuTT [PCIG09-GA-2011-293643]
- Sao Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo) [2011/11640-5, 2011/51684-1]
- Brazil's National Council for Scientific and Technological Development
- Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior
- Engineering and Physical Sciences Research Council program grant CAPITALS [EP/J017566/1]
- EPSRC [EP/J017566/1] Funding Source: UKRI
- Engineering and Physical Sciences Research Council [EP/J017566/1] Funding Source: researchfish
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.
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