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More on the Biology, Chemistry and Medicine of HAMLET (Human
Alpha-lactalbumin Made LEthal to Tumour cells)
Endogenous human alpha-lactalbumin is complexed with a
calcium ion and serves as a cofactor in lactose synthesis, but has
no tumoricidal properties. The alpha-lactalbumin must be partially
unfolded to allow for release of the calcium ion and replacement
with an oleic acid molecule. The partially folded conformation is
essential to the cytotoxicity of HAMLET, as mutagenesis studies
have shown that completely unfolded alpha-lacalbumin does not
retain the functional properties of HAMLET. The oleic acid is
necessary for stabilizing this molecule in this partially unfolded
state.
HAMLET carries out independent attacks on many distinct cell
organelles, including mitochondria, proteasomes, and histones, and
interferes with cell processes such as macroautophagy. It has been
shown that HAMLET binds to the cell surface and rapidly invades
cells, with tumor cells taking up far more protein than healthy,
differentiated cells. The mechanism of its entry is poorly
understood, but recent studies indicate that the oleic acid in the
HAMLET complex interacts with phosphatidylserine and o-glycosylated
mucin on the plasma membrane, both of which are expressed in
greater amounts on the plasma membrane of tumor cells, possibly
providing for HAMLET’s specificity.
One of the most prominent targets of HAMLET once inside the
cell is the mitochondrion. Electron microscopy has revealed
physical damage to the mitochondrial membranes and assays have
found cytochrome c release and activation of the caspase cascade,
the most notable ones being caspases 2, 3, and 9. It is interesting
to note that cell death is not prevented by caspase inhibitors, or
by BCL-2 or p53 mutagenesis, indicating that the traditional
apoptotic caspase cascade is not the ultimate cause of cell
death.
Another target of HAMLET is the proteasome. 26S proteasomes
are activated in response to large quantities of unfolded HAMLET
protein in the cytoplasm, but degradation of HAMLET by the
proteasome is unusually slow. Furthermore, in vitro studies have
shown that HAMLET is capable of binding the catalytic 20S subunit
of the proteasome and disabling its enzymatic activity, an effect
that has never before been demonstrated for any protein. However,
proteasome inhibition alone does not seem to be responsible for
HAMLET-induced cell death, as proteasome inhibitors have been shown
to reduce the cytotoxicity of HAMLET.
HAMLET also targets the nucleus, where it interacts with
histones to interfere with transcriptional processes. Studies have
shown that HAMLET is mostly localized to the nucleus within one
hour of invading a tumor cell. Hamlet has been shown to bind with
high affinity to individual histone proteins, to be specific H2a,
H2b, H3, and H4, as well as entire nucleosomal units. This
interaction irreversibly blocks transcription and leads to
activation of p53. This process has been demonstrated to be similar
to histone hyperacetylation and it was found that histone
de-acetylase inhibitors potentiated the effects of HAMLET.
HAMLET cells showed the physiological characteristics of
macroautophagy, a process in which cellular components are
sequestered in double membrane-bound vesicles that fuse with
lysosomes for degradation. Cells also showed decreased levels of
mTOR, a known inhibitor of macroautophagy. HAMLET cells and cells
under conditions of amino acid starvation (a known initiator of
macroautophagy) showed similar expression patterns of
autophagocytotic proteins and responded equally well to addition of
macroautophagy inhibitors.
https://en.wikipedia.org/wiki/HAMLET_(protein_complex)
