Book of abstract 2008

Lysosomal protease-mediated killing of cells: possible use in cancer
therapy?
Boris Turk
Dept. of Biochemistry and Molecular and Structural Biology, Ljubljana, Slovenia
Cancer cells are known to evade clearance by apoptosis. There are numerous mechanism
utilized by cancerous cells to escape apoptosis, including p53 mutations and/or
degradation, upregulation of antiapoptotic Bcl2 homologs and upregulation of IAPs.
Although seemingly different, caspase activation is much less efficient in all of them. There
is mounting evidence that in addition to caspases cysteine cathepsins play an important
role in apoptosis. Lysosomal destabilization, accompanied by the release of cathepsins
into cytosol, was often found to be an early event in apoptotic cascade, preceding other
hallmarks of apoptosis including mitochondrial outer membrane permeabilization and
caspase activation. Bid and other members of Bcl2 family were found to be important
messengers of the signal, whereas other cathepsin substrates, which could explain potential
role of cathepsins in caspase-independent cell death were not identified as yet. Using
lysosomotropic compound LeuLeuOMe as a model, we were able to show that apoptotic
cell death is almost completely abolished in the absence of mitochondrial membrane
permeabilization with cathepsins B and L being the major players. This suggests that
cysteine cathepsins predominantly trigger apoptosis through MMP and subsequent caspase
activation and not through caspase-independent pathways, which could provide a potential
for clearance of cancer cells, where Bcl-2 homologs and/or IAPs are upregulated.
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