Ovarian Cancer Metabolism: Effect of Anoikis Condition and Nitric Oxide on Ovarian Cancer Metabolism, and Effect of Metabolites on Ovarian Cancer Migration
Doctor of Philosophy
Ovarian cancer remains the most lethal gynecological malignancy worldwide, with most of the disease detected at later stages. Elucidating pathways based on upregulation of proteins and genes involved in the development and progression of ovarian cancer is underway. However, understanding of the metabolic regulation and changes in metabolism involved in ovarian cancer is lacking, and this understanding could lead to development of therapies for ovarian cancer. In order for ovarian cancer cells to metastasize, they must be able to survive deprived of extracellular matrix attachment in the peritoneal cavity. In the first part of this thesis, the effect of cell detachment on the metabolism of highly-invasive and less-invasive ovarian cancer cells was explored by employing culture methods that induced cell detachment. Experiments were designed to collect media from the cells for metabolic analysis to gain insight into changes in the glycolytic and oxidative phosphorylation pathways. Results showed that oxidative phosphorylation was higher for highly-invasive versus less-invasive ovarian cancer cells in detachment. It was also observed that highly-invasive ovarian cancer cells consumed more pyruvate than less-invasive ovarian cancer cells, which indicated that the ovarian cancer cells had functional mitochondria. In the second part of this thesis, the role of metabolites in cancer cell migration was investigated. Results showed that pyruvate increased the cancer cell migration, indicating that mitochondria were important for the migration of ovarian cancer cells. In the last part of this thesis, the role of nitric oxide on ovarian cancer cell proliferation and metabolism was explored. Results showed that nitric oxide increased proliferation of ovarian cancer cells, and also maintained their high glycolytic rate (i.e. – the Warburg Effect). This was paired with a decrease in oxidative phosphorylation, which was due to inhibition by nitric oxide of complexes II/III and complex IV in the mitochondria. Thus, nitric oxide plays an important role in the metabolism of ovarian cancer cells. Our work is one of the first to elucidate the interactions between non-adherent/nitric oxide stress and ovarian cancer metabolism, and could pave the way for development of metabolically-based therapies that could halt progression of ovarian cancer.