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INVESTIGATING THE EFFECTS OF ENVIRONMENTAL CONDITIONS ON PIM1 DNA STRUCTURES AND THE DOXORUBICIN BINDING
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Thesis (Saba Orouji)_20240613.pdf
Date
2024-6-07
Author
OROUJI, SABA
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Triple negative breast cancer (TNBC), which lacks the ER, PR and HER-2 expressions is accounted for the 25% of all breast cancer related deaths in 2019. PIM1 oncogenes were found to be overexpressed in TNBC and PIM1 sequences were found to adopt unique G-quadruplex-duplex hybrid type secondary structures. Within the scope of this thesis, first the effect of pH and ions on the secondary structures of the three PIM1 gene sequences was investigated using UV-Vis and CD spectroscopy. All three sequences were found to be stable under the conditions investigated, and plausibly coexist together. The lower pH was found to be stabilizing the i-motif structure. The stabilization of G4s by K+ cations compared to Na+ was significant. The interactions between the Doxorubicin (Dox) and these secondary structures were investigated via UV-Vis, CD and Fluorescence spectroscopy experiments in the second part. The affinity of Dox towards different nucleic acid structures was also investigated via competition dialysis experiments. Our investigations revealed that Dox exhibited almost equal affinity for all PIM1 gene secondary structures. It was found to be stabilizing all the secondary structures to a great extent. This is the first study revealing the formation of the i-motif structures in the PIM1 sequences and the binding of Dox to them, suggesting a potential new mechanism of action for Dox in-vivo. We believe our studies will shed light on and contribute to ongoing research on the potential of PIM1 to be a target for TNBC treatment.
Subject Keywords
Breast cancer, PIM1, G-quadruplex, i-motif, Doxorubicin
URI
https://hdl.handle.net/11511/109869
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Graduate School of Natural and Applied Sciences, Thesis
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S. OROUJI, “INVESTIGATING THE EFFECTS OF ENVIRONMENTAL CONDITIONS ON PIM1 DNA STRUCTURES AND THE DOXORUBICIN BINDING,” M.S. - Master of Science, Middle East Technical University, 2024.
