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Title: Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex

Abstract

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. In conclusion, 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.

Authors:
 [1];  [2];  [2];  [3];  [1];  [2];  [4];  [4];  [1];  [5];  [1]
+ Show Author Affiliations
  1. Lund Univ., Lund (Sweden)
  2. Univ. of California, Davis, CA (United States)
  3. Lund Univ., Lund (Sweden); Nanyang Technological Univ. (Singapore)
  4. Univ. of Copenhagen, Copenhagen (Denmark)
  5. Univ. of California, Davis, CA (United States); Nanyang Technological Univ. (Singapore)
Publication Date:
Research Org.:
Univ. of California, Davis, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1241901
Grant/Contract Number:  
FG02-04ER46173
Resource Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; liquid signalling; membrane biophysics

Citation Formats

Nadeem, Aftab, Sanborn, Jeremy, Gettel, Douglas L., James, Ho C. S., Rydström, Anna, Ngassam, Viviane N., Klausen, Thomas Kjaer, Pedersen, Stine Falsig, Lam, Matti, Parikh, Atul N., and Svanborg, Catharina. Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex. United States: N. p., 2015. Web. doi:10.1038/srep16432.
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Nadeem, Aftab, Sanborn, Jeremy, Gettel, Douglas L., James, Ho C. S., Rydström, Anna, Ngassam, Viviane N., Klausen, Thomas Kjaer, Pedersen, Stine Falsig, Lam, Matti, Parikh, Atul N., & Svanborg, Catharina. Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex. United States. https://doi.org/10.1038/srep16432
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Nadeem, Aftab, Sanborn, Jeremy, Gettel, Douglas L., James, Ho C. S., Rydström, Anna, Ngassam, Viviane N., Klausen, Thomas Kjaer, Pedersen, Stine Falsig, Lam, Matti, Parikh, Atul N., and Svanborg, Catharina. Thu . "Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex". United States. https://doi.org/10.1038/srep16432. https://www.osti.gov/servlets/purl/1241901.
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@article{osti_1241901,
title = {Protein receptor-independent plasma membrane remodeling by HAMLET: A tumoricidal protein-lipid complex},
author = {Nadeem, Aftab and Sanborn, Jeremy and Gettel, Douglas L. and James, Ho C. S. and Rydström, Anna and Ngassam, Viviane N. and Klausen, Thomas Kjaer and Pedersen, Stine Falsig and Lam, Matti and Parikh, Atul N. and Svanborg, Catharina},
abstractNote = {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. In conclusion, 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.},
doi = {10.1038/srep16432},
journal = {Scientific Reports},
number = ,
volume = 5,
place = {United States},
year = {Thu Nov 12 00:00:00 EST 2015},
month = {Thu Nov 12 00:00:00 EST 2015}
}
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https://doi.org/10.1038/srep16432
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GUV preparation and imaging: Minimizing artifacts
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α-Lactalbumin species variation, HAMLET formation, and tumor cell death
journal, June 2006

  • Pettersson, Jenny; Mossberg, Ann-Kristin; Svanborg, Catharina
  • Biochemical and Biophysical Research Communications, Vol. 345, Issue 1
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Interaction of antitumor α-lactalbumin—oleic acid complexes with artificial and natural membranes
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    Efficiency of novel nanocombinations of bovine milk proteins (lactoperoxidase and lactoferrin) for combating different human cancer cell lines
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    journal, December 2017

    BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state
    journal, August 2018

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