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HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.

Aits, Sonja LU ; Gustafsson, Lotta LU ; Hallgren, Oskar LU ; Brest, Patrick LU ; Gustafsson, Mattias LU ; Trulsson, Maria LU ; Mossberg, Anki LU ; Simon, Hans-Uwe; Mograbi, Baharia and Svanborg, Catharina LU (2009) In International Journal of Cancer 124(5). p.1008-1019
Abstract
HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western... (More)
HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
International Journal of Cancer
volume
124
issue
5
pages
1008 - 1019
publisher
John Wiley & Sons
external identifiers
  • wos:000263077900003
  • pmid:19048621
  • scopus:58749114573
ISSN
0020-7136
DOI
10.1002/ijc.24076
language
English
LU publication?
yes
id
9fa75fde-6e57-4878-b25b-6e80eefb8c11 (old id 1276582)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19048621?dopt=Abstract
date added to LUP
2009-01-09 08:24:31
date last changed
2017-10-01 04:58:11
@article{9fa75fde-6e57-4878-b25b-6e80eefb8c11,
  abstract     = {HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.},
  author       = {Aits, Sonja and Gustafsson, Lotta and Hallgren, Oskar and Brest, Patrick and Gustafsson, Mattias and Trulsson, Maria and Mossberg, Anki and Simon, Hans-Uwe and Mograbi, Baharia and Svanborg, Catharina},
  issn         = {0020-7136},
  language     = {eng},
  number       = {5},
  pages        = {1008--1019},
  publisher    = {John Wiley & Sons},
  series       = {International Journal of Cancer},
  title        = {HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.},
  url          = {http://dx.doi.org/10.1002/ijc.24076},
  volume       = {124},
  year         = {2009},
}