Abstract
BackgroundNeopetrosiamide A (NeoA) is a 28-amino acid tricyclic peptide originally isolated from a marine sponge as a tumor cell invasion inhibitor whose mechanism of action is unknown.Methodology/Principal FindingsWe show that NeoA reversibly inhibits tumor cell adhesion, disassembles focal adhesions in pre-attached cells, and decreases the level of β1 integrin subunits on the cell surface. NeoA also induces the formation of dynamic, membrane-bound protrusions on the surface of treated cells and the release of membrane-bound vesicles into the culture medium. Proteomic analysis indicates that the vesicles contain EGF and transferrin receptors as well as a number of proteins involved in adhesion and migration including: β1 integrin and numerous α integrin subunits; actin and actin-binding proteins such as cofilin, moesin and myosin 1C; and membrane modulating eps15 homology domain (EHD) proteins. Surface labeling, trafficking inhibition, and real-time imaging experiments all suggest that β1 integrin-containing vesicles are released directly from NeoA-induced cell surface protrusions rather than from vesicles generated intracellularly. The biological activity of NeoA is dependent on its disulfide bond pattern and NMR spectroscopy indicates that the peptide is globular with a continuous ridge of hydrophobic groups flanked by charged amino acid residues that could facilitate a simultaneous interaction with lipids and proteins in the membrane.Conclusions/SignificanceNeoA is an anti-adhesive peptide that decreases cell surface integrin levels through a novel, yet to be elucidated, mechanism that involves the release of adhesion molecule-containing vesicles from the cell surface.
Highlights
The ability of tumor cells to interact dynamically with the extracellular matrix (ECM) is an important driver of invasion and metastasis [1]
A number of compounds have been developed that block the ability of integrins to bind to their cognate ECM ligands, including peptides based on the Arg-Gly-Asp (RGD) sequence found within many ECM proteins [2,3] and integrinblocking antibodies [4]
Neopetrosiamide A (NeoA) triggers the rapid formation of membranous protrusions on the cell surface and the release of membrane-bound vesicles that contain a number of integrin subunits, adhesionassociated proteins, and growth factor receptors
Summary
The ability of tumor cells to interact dynamically with the extracellular matrix (ECM) is an important driver of invasion and metastasis [1]. In addition to inhibiting tumor cell invasion, NeoA inhibits tumor cell adhesion to rigid ECM substrata and it causes pre-attached cells to round up and retract from the substratum The latter retraction is associated with dissolution of focal adhesions and a decrease in cell surface b1 integrins. NeoA triggers the rapid formation of membranous protrusions on the cell surface and the release of membrane-bound vesicles that contain a number of integrin subunits, adhesionassociated proteins, and growth factor receptors. These effects of NeoA are rapidly induced, within minutes, before any cytotoxicity can be observed, and they are reversible upon peptide removal. Neopetrosiamide A (NeoA) is a 28-amino acid tricyclic peptide originally isolated from a marine sponge as a tumor cell invasion inhibitor whose mechanism of action is unknown
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