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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1021511
- author
- Hallgren, Oskar
LU
; Aits, Sonja
LU
; Brest, Patrick
LU
; Gustafsson, Lotta
LU
; Mossberg, Anki
LU
; Wullt, Björn
LU
and Svanborg, Catharina
LU
- organization
- publishing date
- 2008
- type
- Contribution to journal
- publication status
- 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
- Springer
- external identifiers
-
- pmid:18183931
- wos:000252397100008
- scopus:84934444496
- pmid:18183931
- ISSN
- 0065-2598
- DOI
- 10.1007/978-0-387-74087-4_8
- project
- HAMLET- In vivo effects and mechanisms of tumor cells death
- 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
- 2016-04-01 13:04:09
- date last changed
- 2022-01-27 17:06:37
@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}},
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}},
language = {{eng}},
pages = {{217--240}},
publisher = {{Springer}},
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}},
doi = {{10.1007/978-0-387-74087-4_8}},
volume = {{606}},
year = {{2008}},
}