TY - JOUR
T1 - HAMLET kills tumor cells by an apoptosis-like mechanism - Cellular, molecular, and therapeutic aspects
AU - Svanborg, Catharina
AU - Ågerstam, Helena
AU - Aronson, Annika
AU - Bjerkvig, Rolf
AU - Düringer, Caroline
AU - Fischer, Walter
AU - Gustafsson, Lotta
AU - Hallgren, Oskar
AU - Leijonhuvud, Irene
AU - Linse, Sara
AU - Mossberg, Ann Kristin
AU - Nilsson, Hanna
AU - Pettersson, Jenny
AU - Svensson, Malin
N1 - Funding Information:
These studies were supported by grants from the Lund Family donation to the American Cancer Society (Grant number, SPIRG-97-157-05 and 97-158-05), The Swedish Cancer Foundation (grants number, 3807-B97-01XAB CS, 3807-B01-06XCC, 4633-B01-01XAB1), the Swedish Pediatric Cancer Foundation, The Medical Faculty, Lund University,T he Segerfalk, Lundgren, and Wallenberg Foundations.
PY - 2003
Y1 - 2003
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037235684&partnerID=8YFLogxK
U2 - 10.1016/S0065-230X(03)88302-1
DO - 10.1016/S0065-230X(03)88302-1
M3 - Review article
C2 - 12665051
AN - SCOPUS:0037235684
SN - 0065-230X
VL - 88
SP - 1
EP - 29
JO - Advances in Cancer Research
JF - Advances in Cancer Research
ER -