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HAMLET: functional properties and therapeutic potential.

Ho Cs, James; Rydström, Anna LU ; Trulsson, Maria LU ; Bålfors, Johannes LU ; Storm, Petter LU ; Puthia, Manoj LU ; Nadeem, Aftab LU and Svanborg, Catharina LU (2012) In Future Oncology 8(10). p.1301-1313
Abstract
Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for... (More)
Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Future Oncology
volume
8
issue
10
pages
1301 - 1313
publisher
Future Medicine Ltd.
external identifiers
  • wos:000310717700014
  • pmid:23130929
  • scopus:84868556728
ISSN
1479-6694
DOI
10.2217/fon.12.122
language
English
LU publication?
yes
id
63267516-5c80-4618-99dc-d96ad4d9be01 (old id 3219208)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23130929?dopt=Abstract
date added to LUP
2012-12-03 13:14:49
date last changed
2017-04-09 04:30:36
@article{63267516-5c80-4618-99dc-d96ad4d9be01,
  abstract     = {Human α-lactalbumin made lethal to tumor cells (HAMLET) is the first member in a new family of protein-lipid complexes that kills tumor cells with high selectivity. The protein component of HAMLET is α-lactalbumin, which in its native state acts as a substrate specifier in the lactose synthase complex, thereby defining a function essential for the survival of lactating mammals. In addition, α-lactalbumin acquires tumoricidal activity after partial unfolding and binding to oleic acid. The lipid cofactor serves the dual role as a stabilizer of the altered fold of the protein and a coactivator of specific steps in tumor cell death. HAMLET is broadly tumoricidal, suggesting that the complex identifies conserved death pathways suitable for targeting by novel therapies. Sensitivity to HAMLET is defined by oncogene expression including Ras and c-Myc and by glycolytic enzymes. Cellular targets are located in the cytoplasmic membrane, cytoskeleton, mitochondria, proteasomes, lysosomes and nuclei, and specific signaling pathways are rapidly activated, first by interactions of HAMLET with the cell membrane and subsequently after HAMLET internalization. Therapeutic effects of HAMLET have been demonstrated in human skin papillomas and bladder cancers, and HAMLET limits the progression of human glioblastomas, with no evidence of toxicity for normal brain or bladder tissue. These findings open up new avenues for cancer therapy and the understanding of conserved death responses in tumor cells.},
  author       = {Ho Cs, James and Rydström, Anna and Trulsson, Maria and Bålfors, Johannes and Storm, Petter and Puthia, Manoj and Nadeem, Aftab and Svanborg, Catharina},
  issn         = {1479-6694},
  language     = {eng},
  number       = {10},
  pages        = {1301--1313},
  publisher    = {Future Medicine Ltd.},
  series       = {Future Oncology},
  title        = {HAMLET: functional properties and therapeutic potential.},
  url          = {http://dx.doi.org/10.2217/fon.12.122},
  volume       = {8},
  year         = {2012},
}