Protein receptor-independent plasma membrane remodeling by HAMLET: a tumoricidal protein-lipid complex.

Autor: Nadeem A; Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden., Sanborn J; Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA., Gettel DL; Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA., James HC; Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.; Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singapore., Rydström A; Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden., Ngassam VN; Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA., Klausen TK; Department of Biology, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark., Pedersen SF; Department of Biology, University of Copenhagen, Universitetsparken 13, 2100, Copenhagen, Denmark., Lam M; Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden., Parikh AN; Departments of Applied Science, Biomedical Engineering, and Chemical Engineering &Materials Science, University of California, Davis, CA 95616 USA.; Centre for Biomimetic Sensor Science, School of Materials Science and Engineering, Nanyang Technological University, 50 Nanyang Drive, 637553, Singapore., Svanborg C; Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, S-223 62 Lund, Sweden.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2015 Nov 12; Vol. 5, pp. 16432. Date of Electronic Publication: 2015 Nov 12.
DOI: 10.1038/srep16432
Abstrakt: A central tenet of signal transduction in eukaryotic cells is that extra-cellular ligands activate specific cell surface receptors, which orchestrate downstream responses. This ''protein-centric" view is increasingly challenged by evidence for the involvement of specialized membrane domains in signal transduction. Here, we propose that membrane perturbation may serve as an alternative mechanism to activate a conserved cell-death program in cancer cells. This view emerges from the extraordinary manner in which HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) kills a wide range of tumor cells in vitro and demonstrates therapeutic efficacy and selectivity in cancer models and clinical studies. We identify a ''receptor independent" transformation of vesicular motifs in model membranes, which is paralleled by gross remodeling of tumor cell membranes. Furthermore, we find that HAMLET accumulates within these de novo membrane conformations and define membrane blebs as cellular compartments for direct interactions of HAMLET with essential target proteins such as the Ras family of GTPases. Finally, we demonstrate lower sensitivity of healthy cell membranes to HAMLET challenge. These features suggest that HAMLET-induced curvature-dependent membrane conformations serve as surrogate receptors for initiating signal transduction cascades, ultimately leading to cell death.
Databáze: MEDLINE
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