Laboratory for Genotoxic Agents
We are a young and dynamic laboratory, one of the biggest laboratories in the Division of Molecular Biology, consisting of two research groups working on different subjects with some degree of overlap. We collaborate with several researchers groups within the Institute and even more research groups abroad (Germany, France, USA, Slovenia). We use state-of-the-art cell biology, molecular biology and biochemistry techniques.
The directions of our research are:
1) Integrin signaling in cancer cell chemoresistance
2) Cell response to genotoxic agents and mechanisms involved in drug resistance
3) The involvement of miRNA in cancer in sensitivity to anticancer drugs
4) Adenoviruses as vectors for gene transfer
5) New synthesized compounds as potential anticancer drugs
Group Osmak Maja: Cell response to cytotoxic agents and development of drug resistance
Cell exposure to cytotoxic compounds can cause diverse harmful effects. After cell exposure to such agents, complex network of protective, precisely controlled and interdependent signalling cascades is induced. In drug resistant cells the protective mechanisms are more expressed. Our investigation is focused on the signaling cascades that are induced by cytotoxic agents, specially in drug-resistant cells: early membrane changes, the activation of Rho GTPases, induction of mitogen activated protein kinases, DNA damage repair, and eventually, the induction of cell death. The role of cell status is examined as well: cell adhesion, the activity of transmembrane transport proteins, redox state, and the activity/alterations in the genes involved in DNA damage repair and cell death.
Group Ambriović Ristov Andreja: Increase of adenovirus transduction efficacy and resistance to cytostatics
Using model of HEp2-derived αvβ3 integrin-expressing cells we have shown that integrin αvβ3 is involved in the appearance of resistance to several anticancer drugs (cisplatin, mitomycin C, and doxorubicin). In addition, we described a novel mechanism mediated by integrin αvβ3 that regulates cell sensitivity to anticancer drugs which generate reactive oxygen species. We are currently investigating the signal transduction pathway triggered by integrin αvβ3 that leads to antitumor drug resistance. We are also trying to find out whether similar mechanism exists in a different cell model of head and neck tumor cells.
One strategy for genetic retargeting of adenovirus type 5 is based on the modification of Ad5 tropism by genetic incorporation of a targeting ligand into the adenovirus fiber protein. We are interested in two retargeting motifs: NGR that binds to aminopeptidase N and RGD that binds to αv integrins. In addition we are currently investigating the possibility of retargeting adenoviruses to integrin α4β1.
Data from literature and our own data suggested that adenovirus type 5 (Ad5) mediated gene transfer is more efficacious for cancer cells resistant to anticancer drugs as compared to parental cell line. We are currently investigating mechanisms of increased Ad5-mediated transgene expression of cell clones resistant to different anticancer drugs. We are also interested in the influence of primary Ad5 receptor (coxsackie adenovirus receptor) overexpression on αv integrins, cell adhesion and migration.