Adaptations to glutamine deprivation in cancer and its use as a dietary supplement in cancer therapeutics
- Author(s): Ishak Gabra, Mari Boules
- Advisor(s): Kong, Mei
- et al.
Tumors reprogram pathways of nutrient acquisition and metabolism to meet their bioenergetic needs and fast proliferation. Glutamine, a non-essential amino acid, was shown to contribute to several core metabolic pathways, as well as epigenetic modifications, in proliferating tumor cells. However, neovasculature development in growing tumors fail to deliver oxygen and key nutrients, such as glutamine, to regions of solid tumors. Concurrently, increased glutamine utilization in cancer cells often lead to its depletion. Similar to hypoxia, cancer cells initiate remodeling of metabolism and gene expression to adapt to these periods of glutamine deprivation.
This dissertation will present recent understanding of nutrient stress in the microenvironment, with special focus on glutamine metabolism, and the role of glutamine metabolism in supporting deregulated epigenetics in cancer. Specifically, we demonstrate a potential survival mechanism mediated by an IKKβ-p53 signaling axis in cancer upon glutamine deprivation. We found that, upon glutamine depletion, IKKβ can directly phosphorylate p53 on Serine 392, which activates it, independent of the NF-κB pathway. The newly identified IKKβ-p53 signaling axis is necessary in mediating survival through the upregulation of p53 downstream genes.
Finally, we investigate the therapeutic potential of using dietary glutamine supplementation to inhibit tumor growth by exploiting the protean role of glutamine in cancer metabolism and epigenetics. Our results indicate glutamine supplementation in melanoma tumors downregulates the expression of oncogenes via epigenetic reprogramming and cooperates with targeted therapies. These results further solidify the connection between metabolites and epigenetic changes that can be detrimental to cancer cells that adapted to glutamine deprivation in their microenvironment.