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Mushrooms as a source <strong>of</strong> antitumour substances<br />
Jerica Sabotič1, Jože Brzin1, Petra Avanzo1, Tatjana Popovič1, Janko Kos1 ,2<br />
1Dept. <strong>of</strong> Biotechnology, Jožef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia; 2Dept. <strong>of</strong><br />
Pharmaceutical Biology, Faculty <strong>of</strong> Pharmacy, University <strong>of</strong> Ljubljana, Aškerčeva 7, 1000 Ljubljana,<br />
Slovenia<br />
For centuries, mushrooms have been valued as an edible and medical resource. They<br />
represent a vast and yet largely untapped source <strong>of</strong> powerful new pharmaceutical products.<br />
Among the most important ones are substances with immunomodulatory and antitumour<br />
properties, <strong>of</strong> which high molecular weight polysaccharides are the best known, although<br />
fungal lectins have recently gained some research attention. Our research is focused on<br />
proteolytic systems <strong>of</strong> higher basidiomycetes. We have shown that mushrooms are a rich<br />
source <strong>of</strong> diverse proteases and their inhibitors that show unique features possibly exclusive<br />
to basidiomycetes.<br />
Proteolytic enzymes play important part in tumour progression. Four families <strong>of</strong> proteases<br />
have been implicated in the process <strong>of</strong> tumour progression and metastasis, namely matrix<br />
metalloproteases, cysteine proteases, serine proteases and aspartic proteases. Cysteine<br />
cathepsins, lysosomal cysteine proteases, have been implicated in multiple steps <strong>of</strong> tumour<br />
progression, including processes <strong>of</strong> cell transformation and differentiation, motility,<br />
adhesion, invasion, angiogenesis and metastasis. Cysteine cathepsins are promising<br />
drug targets for treating cancer, however due to complexity <strong>of</strong> their pathophysiological<br />
roles, understanding appropriate cysteine cathepsins to target at each stage <strong>of</strong> tumour<br />
development and progression is crucial for development <strong>of</strong> specific inhibitors for<br />
therapeutic use. Protein inhibitors <strong>of</strong> cysteine proteases from basidiomycetes <strong>of</strong>fer unique<br />
biochemical features and inhibitory spectra unlike that <strong>of</strong> any other family <strong>of</strong> cysteine<br />
protease inhibitors. Clitocypin, cysteine protease inhibitor from the mushroom clouded<br />
agaric (Clitocybe nebularis), for example, inhibits cathepsins L and K, but does not inhibit<br />
p40<br />
cathepsins B and H.<br />
Recently, serine proteases, namely tissue kallikreins, have also been directly linked to<br />
neoplastic progression, similarly as cathepsins showing stimulatory or inhibitory effects in<br />
many phases <strong>of</strong> tumour progression. Protein inhibitor <strong>of</strong> serine proteases, CNSPI from the<br />
clouded agaric mushroom (Clitocybe nebularis serine protease inhibitor) exhibits unique<br />
biochemical and inhibitory properties, as it strongly inhibits trypsin and chimotrypsin,<br />
weakly pancreatic kallikrein while elastase is not affected.<br />
Mushroom-derived protein inhibitors <strong>of</strong> cysteine or serine proteases that show unique<br />
features <strong>of</strong> selectivity and specificity reveal mushrooms as a valuable source <strong>of</strong> protease<br />
inhibitors that could find use in research towards understanding the role <strong>of</strong> individual<br />
proteases in different stages <strong>of</strong> tumour progression as well as in drug development and<br />
design for anti-tumour or antiprotease therapy <strong>of</strong> cancer patients.<br />
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