Doctor of Philosophy (PhD)


Biological Sciences

Document Type



PFKFB3, an isoform of PFK-2, which is highly expressed in cancer cells, has been suggested to be associated with enhanced aerobic glycolysis in cancer by elevating the intracellular levels of key glycolytic activator, Fru-2,6-P2. This work describes the importance of PFKFB3 function in metabolic alterations and adaptations of cancers, providing new insights into the PFKFB3-associated ROS regulation in cancer and suggesting promising strategies for cancer drug development. The first study investigates the therapeutic potential of novel PFKFB3 inhibitors as well as the molecular mechanism of PFKFB3 inhibition. I was able to identify small molecular inhibitors, N4A and YN1, which almost constantly inhibit PFKFB3 and ultimately lead to cancer cell death. I determined the crystal structure of PFKFB3 in complex with those inhibitors and these structures revealed the molecular mechanism of inhibitor-recognition by PFKFB3. Providing direct information on the interaction between a potential drug molecule and its target protein at the molecular level, this study established a framework for future development efforts and validated PFKFB3 as a target for new cancer therapies. The second study investigates the functional involvement of PFKFB3 in ROS regulation within cancer cells. We found PFKFB3 to be S-glutathionylated under excessive oxidative stress, which leads to inactivation of the kinase activity of PFKFB3 Consequently, the activation of PFKFB3, induced by S-glutathionylation, decreases cellular Fru-2,6-P2 levels and reroutes the glucose metabolic flux from glycolysis to the PPP, maintaining oxidative homeostasis in cancer cells. The ability of PFKFB3 to control ROS levels can not only support cancer cell survival but also maintain cell cycle progression. This study provides a new insight into the roles of PFKFB3 as a master switch that senses and controls redox homeostasis in cancer in addition to its role in cancer glycolysis. The functional involvement of PFKFB3 S-glutathionylation in ROS regulation would also suggest a possible role for PFKFB3 in cell cycle progression in cancer cells. Together, this new understanding of PFKFB3 functions in cancer will contribute to the development of appropriate therapeutic strategies for cancer treatment.



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Committee Chair

Lee, Yong-Hwan