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HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.

Svanborg, Catharina LU ; Ågerstam, Helena LU ; Aronson, Annika ; Bjerkvig, Rolf ; Düringer, Caroline LU ; Fischer, Walter ; Gustafsson, Lotta LU orcid ; Hallgren, Oskar LU ; Leijonhuvud, Irene and Linse, Sara LU , et al. (2003) In Advances in Cancer Research 88. p.1-29
Abstract
HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds... (More)
HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Advances in Cancer Research
volume
88
pages
1 - 29
publisher
Elsevier
external identifiers
  • pmid:12665051
  • wos:000182317600001
  • scopus:0037235684
ISSN
0065-230X
language
English
LU publication?
yes
id
22ca745b-3e5e-426f-b489-143223d36ac9 (old id 113663)
alternative location
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7CT1-4F8KFR1-3&_user=745831&_handle=V-WA-A-W-Y-MsSAYVW-UUA-U-AAWWVZCEUW-AAWUUVZDUW-AEVDZWCZY-Y-U&_fmt=summary&_coverDate=01%2F01%2F2003&_rdoc=3&_orig=browse&_srch=%23toc%2318037%232003%23999119999%23557633!&_cdi=18037&view=c&_acct=C000041498&_version=1&_urlVersion=0&_userid=745831&md5=5e06754b820bc08b78f93d294aacd60a
date added to LUP
2016-04-01 16:07:22
date last changed
2022-04-22 19:47:53
@article{22ca745b-3e5e-426f-b489-143223d36ac9,
  abstract     = {{HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.}},
  author       = {{Svanborg, Catharina and Ågerstam, Helena and Aronson, Annika and Bjerkvig, Rolf and Düringer, Caroline and Fischer, Walter and Gustafsson, Lotta and Hallgren, Oskar and Leijonhuvud, Irene and Linse, Sara and Mossberg, Anki and Nilsson, Hanna and Pettersson, Jenny and Svensson, Malin}},
  issn         = {{0065-230X}},
  language     = {{eng}},
  pages        = {{1--29}},
  publisher    = {{Elsevier}},
  series       = {{Advances in Cancer Research}},
  title        = {{HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.}},
  url          = {{http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7CT1-4F8KFR1-3&_user=745831&_handle=V-WA-A-W-Y-MsSAYVW-UUA-U-AAWWVZCEUW-AAWUUVZDUW-AEVDZWCZY-Y-U&_fmt=summary&_coverDate=01%2F01%2F2003&_rdoc=3&_orig=browse&_srch=%23toc%2318037%232003%23999119999%23557633!&_cdi=18037&view=c&_acct=C000041498&_version=1&_urlVersion=0&_userid=745831&md5=5e06754b820bc08b78f93d294aacd60a}},
  volume       = {{88}},
  year         = {{2003}},
}