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Lipids as Tumoricidal Components of Human Alpha-lactalbumin Made Lethal to Tumor Cells (HAMLET); Unique and Shared Effects on Signaling and Death.

Ho Cs, James; Storm, Petter LU ; Rydström, Anna LU ; Bowen, Ben; Alsin, Fredrik; Sullivan, Louise; Ambite, Ines LU ; Mok, Ken Hun; Northen, Trent and Svanborg, Catharina LU (2013) In Journal of Biological Chemistry 288(24). p.17460-17471
Abstract
Long-chain fatty acids (LCFAs) are internalized by receptor-mediated mechanisms or receptor-independent diffusion across cytoplasmic membranes and are utilized as nutrients, building blocks and signaling intermediates. Here we describe how the association of LCFAs to a partially unfolded, extracellular protein can alter the presentation to target cells and cellular effects. HAMLET (Human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded α-lactalbumin and oleic acid (OA). As OA lacks independent tumoridical activity at concentrations equimolar to HAMLET, the contribution of the lipid has been debated. We show by natural abundance 13C NMR that the lipid in HAMLET is deprotonated and by chromatography... (More)
Long-chain fatty acids (LCFAs) are internalized by receptor-mediated mechanisms or receptor-independent diffusion across cytoplasmic membranes and are utilized as nutrients, building blocks and signaling intermediates. Here we describe how the association of LCFAs to a partially unfolded, extracellular protein can alter the presentation to target cells and cellular effects. HAMLET (Human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded α-lactalbumin and oleic acid (OA). As OA lacks independent tumoridical activity at concentrations equimolar to HAMLET, the contribution of the lipid has been debated. We show by natural abundance 13C NMR that the lipid in HAMLET is deprotonated and by chromatography that oleate rather than oleic acid is the relevant HAMLET constituent. Compared to HAMLET, oleate (175 μM) showed weak effects on ion fluxes and gene expression. Unlike HAMLET, which causes metabolic paralysis, fatty acid metabolites were less strongly altered. The functional overlap increased with higher oleate concentrations (500 uM). Cellular responses to OA were weak or absent, suggesting that deprotonation favors cellular interactions of fatty acids. Fatty acids may thus exert some of their essential effects on host cells when in the deprotonated state and when presented in the context of a partially unfolded protein. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
288
issue
24
pages
17460 - 17471
publisher
ASBMB
external identifiers
  • wos:000320380600038
  • pmid:23629662
  • scopus:84879064652
ISSN
1083-351X
DOI
10.1074/jbc.M113.468405
language
English
LU publication?
yes
id
566bc6fc-4f9e-4a16-9c4e-7faf9afb4235 (old id 3805195)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23629662?dopt=Abstract
date added to LUP
2013-06-03 15:32:44
date last changed
2019-03-19 01:15:48
@article{566bc6fc-4f9e-4a16-9c4e-7faf9afb4235,
  abstract     = {Long-chain fatty acids (LCFAs) are internalized by receptor-mediated mechanisms or receptor-independent diffusion across cytoplasmic membranes and are utilized as nutrients, building blocks and signaling intermediates. Here we describe how the association of LCFAs to a partially unfolded, extracellular protein can alter the presentation to target cells and cellular effects. HAMLET (Human α-lactalbumin made lethal to tumor cells) is a tumoricidal complex of partially unfolded α-lactalbumin and oleic acid (OA). As OA lacks independent tumoridical activity at concentrations equimolar to HAMLET, the contribution of the lipid has been debated. We show by natural abundance 13C NMR that the lipid in HAMLET is deprotonated and by chromatography that oleate rather than oleic acid is the relevant HAMLET constituent. Compared to HAMLET, oleate (175 μM) showed weak effects on ion fluxes and gene expression. Unlike HAMLET, which causes metabolic paralysis, fatty acid metabolites were less strongly altered. The functional overlap increased with higher oleate concentrations (500 uM). Cellular responses to OA were weak or absent, suggesting that deprotonation favors cellular interactions of fatty acids. Fatty acids may thus exert some of their essential effects on host cells when in the deprotonated state and when presented in the context of a partially unfolded protein.},
  author       = {Ho Cs, James and Storm, Petter and Rydström, Anna and Bowen, Ben and Alsin, Fredrik and Sullivan, Louise and Ambite, Ines and Mok, Ken Hun and Northen, Trent and Svanborg, Catharina},
  issn         = {1083-351X},
  language     = {eng},
  number       = {24},
  pages        = {17460--17471},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Lipids as Tumoricidal Components of Human Alpha-lactalbumin Made Lethal to Tumor Cells (HAMLET); Unique and Shared Effects on Signaling and Death.},
  url          = {http://dx.doi.org/10.1074/jbc.M113.468405},
  volume       = {288},
  year         = {2013},
}