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Elucidating the role of aquaporins 3 and 5 in the development of breast cancer resistance to oxidative stress

Principal investigator

Project type
Znanstveno-istraživački projekti
Programme
Research Projects
Financier
Croatian Science Foundation
Start date
Jan 15th 2021
End date
Jan 14th 2025
Status
Active
Total cost
984000 HRK
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Discovery of aquaporins, membrane pore which mediate water transport, changed our perception of passive water intake. In mammals, there are 13 isoforms of these tetrameric transmembrane channels. Isomers are grouped regarding their primary structure and specific permeability into three groups: orthodox, utilizing water transport, aquaglyceroporins, mediating glycerol transport and non-orthodox, localized specifically on organelle membranes. In addition to water and glycerol, aquaporins also channel other small, uncharged molecules such as H2O2, urea, NO and CO2. Transport of these molecules can contribute to understanding aquaporin functions: tissue water balance, migration, proliferation and adhesion. These functions inevitably link aquaporins to cancer. In breast cancer, AQP3 localizes by NOX2 which produces H2O2. This H2O2 is then channelled by AQP3 into the cell where it interacts with signalling pathways and stimulates proliferation. In EF receptor expressing cells (EGFR is located in lipid rafts) H2O2 is needed for the EGF-EGFR cascade. Studies show link between aquaporins and certain signalling pathways such as PI3K/Akt in different tumors. Interestingly, there is no dana on the link between aquaporin expression and antioxidative defence. We have previously shown that AQP3 and AQP5 are linked to NRF2 transcription factor, therefore in this project our aim is to clarify the mechanism of this relation. Regulation of intracellular oxidative stress by aquaporins is important in tumor development as oxidative stress cause adaptation to stress further leading to resistance to conventional tumor therapy. Revealing the mechanism oh these two systems can improve our knowledge of the tumor resistance and opens possibility of new adjuvant therapy with better outcome.

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