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Cysteine cathepsins pathways to apoptosis: can one use<br />
them in cancer treatment?<br />
Boris Turk<br />
Jo`ef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia<br />
Apoptosis is the major way of eliminating potentially harmfull and superfluous<br />
cells. The pathway is severely impaired in cancer and cancer cells generally fail<br />
to die. A number of anticancer therapies currently used are therefore aimed to<br />
restore the apoptotic program. There is increasing evidence that at least some<br />
of them induce cell death through lysosomal membrane permeabilization (LMP).<br />
Although cysteine proteases caspases are known to play a major role in the process,<br />
these findings suggest that lysosomal proteases are actively involved in apoptosis.<br />
The most studied cathepsins in this respect are cathepsin B, which is a cysteine<br />
protease, and the aspartic protease cathepsin D. In order to study the molecular<br />
mechanisms of lysosome-induced cell death, we have been using an artificial<br />
detergent (LeuLeu-OMe) to trigger LMP. We were able to show in several cellular<br />
models that selective lysosome disruption with Leu-Leu-OMe resulted in apoptosis,<br />
characterized by lysosome disruption, translocation of lysosomal proteases to the<br />
cytosol and subsequent activation of caspases indirectly through the cleavage of a<br />
proapoptotic Bcl-2 family member Bid and mitochondria disruption. In addition to<br />
Bid, some other cathepsin cellular targets were also identified and will be further<br />
discussed.<br />
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