School of Biomedical Sciences cordially invites you to join the following seminar:

Speaker: Professor Yong-Hwan Lee, Associate Professor of Department of Biological Sciences, Director of Molecular and Cell Biology Resources Core, Louisiana Biomedical Research Network, Louisiana State University at Baton Rouge
Talk Title: Control of energy and oxidative stress homeostasis by PFKFB3 in cancer cells

Date: 30 October 2024 (Wednesday)
Time: 4:00 pm – 5:00 pm
Venue: Lecture Theatre 1, G/F, William M.W. Mong Block, 21 Sassoon Road
Host: Professor Jiandong Huang

Biography

I graduated from Kon-Kuk University, Seoul, Korea, with the BS degree in Animal Sciences in 1989 and finished the Ph.D. degree in Physiology and Biophysics from the State University of New York at Stony Brook. I was trained for the studies of protein structure/function relationships using molecular biology, enzyme kinetics, and protein X-ray crystallography. I made a key role in converting MAD phasing to a routine available to all protein crystallographers. My research area has been extended to structure-based drug design and to system biology, since I joined as a faculty member of LSU. I determined the structures of PFKFB3, the cancer specific isoform of PFKFB, and revealed the molecular basis of Fructose-2,6-bisphosphate synthesis. Based on the model, I developed PFKFB3-specific inhibitors, which were accepted to US Patent as a potential cancer therapeutic. I also elucidated the molecular basis of PFKFB3 deactivation by S-glutathionylation (oxidative stress-dependent covalent modification), which causes metabolic changes for regulation of oxidative stress homeostasis. For these studies, I have extended our field to system biology in which biological significance of a molecular model is tested and confirmed at the cellular level.

Abstract

Fructose-2,6-bisphosphate (F-2,6-P₂) is a potent activator of 6-phosphofructo-1-kinase and cyclin-dependent protein kinase 1, the rate-limiting enzymes of glycolysis and the G₁-to-S phase cell cycle transition, respectively. Both synthesis and hydrolysis of F-2,6-P₂ is catalyzed by the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB). In every mammalian cell, one of the four PFKFB isoforms (PFKFB1-4) is tissue-type specifically expressed as the predominant form. In cancer cells, predominant expression of PFKFB3 is induced by actions of estrogen, progestin, and hypoxia, or by c-myc, c-src, or c-ras-dependent oncogenic cell transformation.

PFKFB3 overexpression causes 5-fold higher F-2,6-P₂ levels and thus plays the key role in cancer hallmarks: the Warburg effect, rapid cell cycle progression, and new blood vessel formation. Its activity is also controlled by post-translational dynamic covalent modifications: activation by phosphorylation at Ser461 and by asymmetrical di-methylation at Arg131 and Arg134 and deactivation by S-glutathionylation at Cys206. Accordingly, PFKFB3 inhibition and, ultimately, down-regulation of F-2,6-P₂ levels has been suggested as a new strategy in fights against cancer.

ALL ARE WELCOME.