Vloga cisteinskih katepsinov pri celičnem signaliziranju (Slovene)

Cancer is one of the most debilitating diseases in the developed world. Despite major investments, mortality is still very high and current therapies are still only partially successful, one of the reasons being insufficient knowledge about the molecular mechanisms leading to cancer progression. Among major factors contributing to cancer development and progression are proteases. In addition to metalloproteases, cysteine cathepsins emerged as major contributing factors, which is largely based on gene ablation animal studies. In addition they also have a critical role in autophagy, which is considered a major survival mechanism of cancer cells. However, molecular mechanisms underlying cancer progression and the involvement of cysteine cathepsins in these processes are still not well understood. The main ideas of this proposal are to identify the cysteine cathepsin signaling pathways in cancer based on the identification of their physiological substrates, to critically evaluate their role in autophagy linked with sensitization of cancer cells to cell death, to explore the potential of novel rapamycin analogues in targeting autophagy and to validate novel tools for selective monitoring of the cathepsin activity in live cells. A long-term goal of the project is to unravel the role of cysteine cathepsins in hyperproliferative disorders such as cancer and their potential in anticancer treatment. This is based on a hypothesis that cysteine cathepsins represent one of the major components of cellular signaling in these processes with a dual role as cell death promoters or cancer promoters. This project should thus provide a fundamental insight into how cysteine cathepsins promote cellular signaling in biological processes leading to cancer. The gained knowledge will significantly contribute to our understanding of the complex biological phenomena and will be instrumental for biomedical research to understand and develop novel strategies to combat cancer and other hyperproliferative diseases, based on the modulation of the activities of the cathepsins or on novel rapamycin analogues with improved properties.

This project was certainly of high biomedical relevance. Lysosomes and lysosomal proteases have already been validated as relevant targets for cancer treatment, whereas several compounds targeting lysosomes and/or lysosomal proteases are already in preclinical or clinical testing. This is true not only for LeuLeuOMe, which entered Phase I clinical trials, but also for siramesine and various antioxidants. We believe that we have opened new avenues in the areas where the exact roles of lysosomes and cathepsins and their signaling pathways were unknown, largely unclear or controversial such as in the caspase independent cell death. The gained knowledge will thus not only significantly contribute to our understanding of the complex biological phenomena, but will in long run also be instrumental in biomedical research to understand and develop novel strategies to combat cancer and other hyperproliferative diseases based on modulation of the activities of lysosomal proteases. In addition, the project strengthened the research at the Department of Biochemistry and Molecular Biology at Jožef Stefan Institute in the field of cell biology and molecular medicine.

Cancer is one of the most debilitating diseases of the developed world. Therapeutic removal of cancer cells by stimulating apoptosis and blocking autophagy, together with the use of protease inhibitors, are currently among the most perspective areas in cancer treatment. In addition, development of Thus, the results obtained will be highly relevant in evaluation of lysosomes and cysteine cathepsins as possible therapeutic and diagnostic targets in cancer. Continuation of the research in representative animal cancer models is therefore of high value for the evaluation of compounds at the preclinical level, which should be interesting for the pharmaceutical companies in Slovenia and abroad. Therefore we can say that although the research performed was largely basic research, it also has its applied component and can be classified as strategic basic research. This is strenghtened by the fact that SME Acies d.o.o. was a partner in the project. Moreover, the work also offered great opportunity for students to be trained in the most advanced methods and areas, such as proteomics (at IJS in our Depatment we have the only protoemics lab in Slovenia), and chemogenomics together with European and other international partners. Both fields have namely high international priority as they are of extreme importance in target identification and validation during drug development. In addition, members of the project have received widespread international recognition, which is very important for the worldwide promotion of Slovenia and as such also for preservation of national identity of Slovenia.