Chapter

Bioactive Components of Milk

Volume 606 of the series Advances in Experimental Medicine and Biology pp 217-240

Apoptosis and Tumor Cell Death in Response to HAMLET (Human α-Lactalbumin Made Lethal to Tumor Cells)

  • Oskar Hallgren
  • , Sonja Aits
  • , Patrick Brest
  • , Lotta Gustafsson
  • , Ann-Kristin Mossberg
  • , Björn Wullt
  • , Catharina SvanborgAffiliated withInstitute of Laboratory Medicine, Section for Microbiology, Immunology and Glycobiology

Abstract

HAMLET (human a-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 a-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 toHAMLET. 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.

Keywords

HAMLET lactalbumin cancer programmed cell death apoptosis macroautophagy Bcl-2 p53 caspase