Tumors cells grow in nutrient and oxygen-deprived microenvironments and adapt to the suboptimal growth conditions by altering their metabolic pathways. The adaptation process commonly creates a tumor phenotype of high glycolytic potential and aggressive growth characteristics which facilitate metastasis and confer resistance to radiation and chemotherapy. Understanding the mechanisms that allow tumors to adapt and survive in their microenvironment is crucial to cancer prevention and control. It was hypothesized that the tumor microenvironment would induce signaling and enzymatic changes, which if manipulated could improve treatment outcome. The results presented here demonstrate that exposure of tumor cells to chronic low pH or hypoxic conditions induced signaling cascades and altered enzyme profiles which resulted in a pro-survival phenotype. Three key adaptation events were observed and included 1) the up regulation of the metabolic stress and glycolytic proteins AMP-activated protein kinase (AMPK) and 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3), respectfully. 2) The upregulation of p53 and 3) changes in the ratios of the bioreductive enzymes were also found to be important in the adaptation. The tumor suppressor p53 played a central role in adaptation because it induced the transcription of anti-glycolytic proteins to control glycolysis and minimize tumor cell acidosis. The ratio of bioreductive enzymes was also altered by changes to the microenvironment. Hypoxia had the greatest effect on protein levels and caused a decrease in the ratio of NAD(P)H:quinone oxidoreductase 1 (NQO1): cytochrome p450 reductase. The increase in cytochrome p450 reductase, a one electron bioreduction enzyme, has been shown to increase toxicity of bioreductive drugs in hypoxic tumors. Micronutrients also had an effect on p53 homeostasis because increasing NQO1 activity by riboflavin supplementation induced a p53-stabilizing effect by enhancing binding of p53 to NQO1, protecting the tumor suppressor from degradation. Taken together, these results indicate the changes that occur in tumor adaptation to the microenvironment require signaling and enzymatic changes that work in concert to regulate metabolism and apoptosis. Many of these changes present therapeutic targets that could be exploited to enhance therapy or prevent adaptation and subsequent tumor growth.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/204113 |
| Date | January 2010 |
| Creators | Mendoza, Erin |
| Contributors | Burd, Randy M, Limesand, Kirsten H., Romagnolo, Donato F., Baker, Amanda F., Guerriero, Vince |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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