HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.
HAMLET (human alpha-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 alpha-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.
Svanborg
Catharina
C
Institute of Laboratory Medicine, Department of Microbiology, Immunology and Glycobiology, Lund University, 221 00 Lund, Sweden.
Agerstam
Helena
H
Aronson
Annika
A
Bjerkvig
Rolf
R
Düringer
Caroline
C
Fischer
Walter
W
Gustafsson
Lotta
L
Hallgren
Oskar
O
Leijonhuvud
Irene
I
Linse
Sara
S
Mossberg
Ann-Kristin
AK
Nilsson
Hanna
H
Pettersson
Jenny
J
Svensson
Malin
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D007477:Ions; D007768:Lactalbumin / Q000627:therapeutic use*; D008055:Lipids; D009368:Neoplasm Transplantation; D019301:Oleic Acid / Q000627:therapeutic use*; D011487:Protein Conformation; D017510:Protein Folding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D007477:Ions; D008055:Lipids; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D019301:Oleic Acid; D007768:Lactalbumin; D002118:Calcium