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Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).

Hallgren, Oskar LU ; Aits, Sonja LU ; Brest, Patrick LU ; Gustafsson, Lotta LU ; Mossberg, Anki LU ; Wullt, Björn LU and Svanborg, Catharina LU (2008) In Advances in Experimental Medicine and Biology 606. p.217-240
Abstract
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release,... (More)
HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET. (Less)
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Contribution to journal
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published
subject
keywords
Apoptosis: drug effects, Lactalbumin: chemistry, Lactalbumin: genetics, Lactalbumin: metabolism, Lactalbumin: pharmacology, Milk, Human: chemistry, Neoplasms: pathology, Oleic Acids: genetics, Oleic Acids: chemistry, Oleic Acids: metabolism, Oleic Acids: pharmacology, Autophagy: drug effects
in
Advances in Experimental Medicine and Biology
volume
606
pages
217 - 240
publisher
Kluwer
external identifiers
  • pmid:18183931
  • wos:000252397100008
  • scopus:84934444496
ISSN
0065-2598
DOI
10.1007/978-0-387-74087-4_8
language
English
LU publication?
yes
id
8b4f7420-a933-425d-983f-693dc601bc97 (old id 1021511)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18183931?dopt=Abstract
date added to LUP
2008-02-08 16:08:01
date last changed
2017-02-22 11:44:15
@article{8b4f7420-a933-425d-983f-693dc601bc97,
  abstract     = {HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.},
  author       = {Hallgren, Oskar and Aits, Sonja and Brest, Patrick and Gustafsson, Lotta and Mossberg, Anki and Wullt, Björn and Svanborg, Catharina},
  issn         = {0065-2598},
  keyword      = {Apoptosis: drug effects,Lactalbumin: chemistry,Lactalbumin: genetics,Lactalbumin: metabolism,Lactalbumin: pharmacology,Milk,Human: chemistry,Neoplasms: pathology,Oleic Acids: genetics,Oleic Acids: chemistry,Oleic Acids: metabolism,Oleic Acids: pharmacology,Autophagy: drug effects},
  language     = {eng},
  pages        = {217--240},
  publisher    = {Kluwer},
  series       = {Advances in Experimental Medicine and Biology},
  title        = {Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).},
  url          = {http://dx.doi.org/10.1007/978-0-387-74087-4_8},
  volume       = {606},
  year         = {2008},
}