Advisor(s)
William Placzek
Committee Member(s)
Chad Petit
Christopher Willey
Gregory Payne
Sunil Sudarshan
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Biochemistry and Molecular Genetics
Date of Award
9-11-2025
Abstract
Hexokinase 2 (HK2) initiates glucose metabolism by catalyzing the conversion of glucose to glucose-6-phosphate providing the starting substrate for a vast array of metabolic pathways such as glycolysis, pentose phosphate pathway (PPP), amino acid biosynthesis and others. While HK2’s metabolic role in normal physiologic function (such as in cardiomyocytes) and cancers (through driving the Warburg Effect) are well established, there is emerging evidence that supports HK2 is also a critical mediator of protein-protein interactions that regulate cell survival. Through comprehensive review, we explore how HK2 contributes to cell survival through metabolic and protein scaffolding roles. We also investigate a novel mechanism of HK2 regulation through the protein-protein interaction between HK2 and the anti-apoptotic Bcl-2 family protein myeloid cell leukemia 1 (MCL1). We demonstrate MCL1 directly binds reverse Bcl-2 homology motifs (rBH3) present on HK2 causing an increase in enzymatic activity. Cellular studies using non-small cell lung cancer models confirmed the biological relevance of this interaction, where we observe significant reductions in glucose-derived metabolites in pathways such as glycolysis, the citric acid cycle, PPP and amino acid biosynthesis. Finally, we observed that the HK2-MCL1 axis promotes cellular metabolic plasticity - allowing non-small cell lung cancer models to adapt to glucose stress. In summary we establish a critical linkage between two key hallmarks of cancer – the ability to evade death and dysregulated metabolism – through the formation of an HK2-MCL1 glucose metabolic regulatory axis.
ProQuest ID
Recommended Citation
Lee, Robert, "Mcl1 And Hexokinase 2 Form A Glucose Metabolic Regulatory Axis" (2025). All ETDs from UAB. 7388.
https://digitalcommons.library.uab.edu/etd-collection/7388
