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Projects / Programmes source: ARIS

The role of cysteine cathepsins in cellular signalling

Research activity

Code Science Field Subfield
1.05.00  Natural sciences and mathematics  Biochemistry and molecular biology   

Code Science Field
B000  Biomedical sciences   

Code Science Field
1.07  Natural Sciences  Other natural sciences 
Keywords
cathepsins, lysosomes, cancer, autophagy, anticancer therapy, molekular mechanism(s), activity-based probes, proteomics
Evaluation (rules)
source: COBISS
Researchers (18)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  34090  PhD Gabriele Droga Mazovec  Biochemistry and molecular biology  Researcher  2014  38 
2.  18801  PhD Marko Fonović  Biochemistry and molecular biology  Researcher  2011 - 2014  188 
3.  25974  PhD Cene Gostinčar  Biotechnology  Researcher  2012  338 
4.  30872  PhD Maruša Hafner Česen  Biochemistry and molecular biology  Beginner researcher  2011 - 2014  31 
5.  14680  PhD Jernej Iskra  Chemistry  Researcher  2013  401 
6.  22312  PhD Gregor Kosec  Biotechnology  Researcher  2011 - 2014  128 
7.  29598  PhD Petra Nikolić  Biochemistry and molecular biology  Researcher  2012 - 2014  64 
8.  13542  PhD Hrvoje Petković  Biotechnology  Researcher  2011 - 2014  301 
9.  35024  PhD Michal Piotr Potempa  Biochemistry and molecular biology  Researcher  2012 - 2013 
10.  34212  PhD Jelena Rajković  Biochemistry and molecular biology  Researcher  2014  21 
11.  21560  PhD Urška Repnik  Microbiology and immunology  Researcher  2011  149 
12.  29542  PhD Barbara Sobotič  Biochemistry and molecular biology  Researcher  2011 - 2014  62 
13.  06058  PhD Stojan Stavber  Chemistry  Researcher  2013  310 
14.  15969  Ivica Štefe  Biochemistry and molecular biology  Technical associate  2011 - 2014  36 
15.  07561  PhD Boris Turk  Biochemistry and molecular biology  Head  2011 - 2014  1,038 
16.  21619  PhD Olga Vasiljeva  Oncology  Researcher  2011 - 2014  183 
17.  32171  PhD Matej Vizovišek  Biochemistry and molecular biology  Junior researcher  2011 - 2014  143 
18.  18286  PhD Tina Zavašnik Bergant  Biochemistry and molecular biology  Researcher  2011 - 2014  138 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,976 
2.  2592  ACIES BIO, biotehnološke raziskave in razvoj, d.o.o. (Slovene)  Ljubljana  2226391  402 
3.  2990  Center of excellence for integrated approaches in chemistry and biology of proteins, Ljubljana  Ljubljana  3663388  727 
Abstract
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.
Significance for science
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.
Significance for the country
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.
Most important scientific results Annual report 2012, 2013, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2011, 2012, 2013, final report, complete report on dLib.si
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