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:
https://lup.lub.lu.se/record/3805195
- author
- 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
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 288
- issue
- 24
- pages
- 17460 - 17471
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000320380600038
- pmid:23629662
- scopus:84879064652
- pmid:23629662
- 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
- 2016-04-01 10:28:13
- date last changed
- 2024-01-06 17:37:52
@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 = {{American Society for Biochemistry and Molecular Biology}},
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 = {{https://lup.lub.lu.se/search/files/1870834/4123888.pdf}},
doi = {{10.1074/jbc.M113.468405}},
volume = {{288}},
year = {{2013}},
}