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Title: Novel functions of NF-κB in cancer
Author: Leow, Shi Chi
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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Cell proliferation involves an active reprogramming of cellular bioenergetic pathways towards glucose metabolism in order to meet the metabolic demands of anabolic growth. NF-κB family of transcription factors coordinate many of the signals that drive proliferation during immunity, inflammation and oncogenesis, but whether NF-κB plays a role in regulating the metabolic reprogramming necessary for cell division during these processes is unknown. In this study, we found that NF-κB functions as a central regulator of energy homeostasis by managing the balance between the utilization of glycolysis and mitochondrial respiration. NF-κB inhibition causes cellular reprogramming to aerobic glycolysis under basal conditions and induces necrosis on glucose deprivation. The metabolic rearrangement that results from NF-κB inhibition bypasses the requirement for tumour suppressor mutation in oncogenic transformation and hinders metabolic adaptation in cancer in vivo. We also identified a mechanism through which NF-κB regulates metabolism and demonstrated the physiological significance of the role of NF-κB in metabolic adaptation in normal and cancerous cells. We also investigated additional functions of NF-κB in oncogenesis mediated via the regulation of telomerase, a tumourigenic factor and downstream target of NF-κB. Telomerase is a ribonucleoprotein enzyme complex that elongates the telomeres of chromosomes to compensate for normal telomeric erosion which occurs at all chromosomes. In recent years, a growing body of evidence has suggested telomere-independent roles of telomerase. Therefore, we sought to investigate whether telomerase also modulated cancer cell metabolism. Our results demonstrate a previously unanticipated role for the catalytic subunit of telomerase, TERT, in regulating the Myc-dependent signalling program which provides one explanation for the role of sustained telomerase activity in human cancer. Given that in cancer, Myc is often a passive conduit for upstream oncogenic flux including that of aberrant NF-κB activity, and global inhibition of both Myc and NF-κB could lead to undersirable toxicities, our data might lead to the development of novel combinatorial cancer treatment modalities.
Supervisor: Tergaonkar, Vinay ; Bubici, concetta ; Franzoso, Guido Sponsor: Agency for Science ; Technology and Research ; Singapore
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available