Metabolic changes during ovarian cancer progression as targets for sphingosine treatment

Abstract

Tumor cells often exhibit an altered metabolic phenotype. However, it is unclear as to when this switch takes place in ovarian cancer, and the potential for these changes to serve as therapeutic targets in clinical prevention and intervention trials. We used our recently developed and characterized mouse ovarian surface epithelial (MOSE) cancer progression model to study metabolic changes in distinct disease stages. As ovarian cancer progresses, complete oxidation of glucose and fatty acids were significantly decreased, concurrent with increases in lactate excretion and 3H-deoxyglucose uptake by the late-stage cancer cells, shifting the cells towards a more glycolytic phenotype. These changes were accompanied by decreases in TCA flux but an increase in citrate synthase activity, providing substrates for de novo fatty acid and cholesterol synthesis. Also, uncoupled maximal respiration rates in mitochondria decreased as cancer progressed. Treatment of the MOSE cells with 1.5μM sphingosine, a bioactive sphingolipid metabolite, decreased citrate synthase activity, increased TCA flux, decreased cholesterol synthesis and glycolysis. Together, our data confirm metabolic changes during ovarian cancer progression, indicate a stage specificity of these changes, and suggest that multiple events in cellular metabolism are targeted by exogenous sphingosine which may be critical for future prevention trials.

Ovarian tumor-initiating cells display a flexible metabolism

“…To offset the proton leak, cells ramp up OCR presenting an indicator of a cell's maximum respiration. As shown in Figure 5, MOSE-L had a significantly decreased FCCP-stimulated OCR compared to the MOSE-E (p<0.001), measured as the difference in FCCP-stimulated OCR minus basal OCR, confirming our previous studies[16]. TICs increased their FCCP stimulated-OCR to the same level as the benign MOSE-E cells (different from MOSE-L p<0.001), indicating that TICs have the capacity to up-regulate OxPhos when necessary after uncoupling, exhibiting an increased OCR reserve.…”

“…We have reported previously that the metabolism of ovarian cancer cells change to a more glycolytic phenotype as the cells progress from a benign to a highly aggressive phenotype[16]. The present studies provide an initial characterization of the metabolic phenotype of highly aggressive ovarian TICs.…”

“…Our previous studies have shown that during progression, the late stage MOSE-L develop a glycolytic phenotype[16], concomitant with increased proliferation and tumorigenicity compared to the non-tumorigenic MOSE-E[14]. This suggests that these changes may be critical for the aggressive phenotype and as such targets for treatment strategies.…”

“…This altered metabolism permits glucose-derived carbon intermediates to be used for macromolecular synthesis to sustain growth[13]. We have recently demonstrated that mouse ovarian surface epithelial (MOSE) cells, representing early (benign), intermediate, and late (aggressive and invasive) stages of ovarian cancer[14, 15] also exhibit an increasingly glycolytic phenotype[16]. As cells progress through distinct stages of the disease, they change their morphology and organization and increase their growth rate while acquiring the ability to grow as spheroids, invade collagen and form tumors in vivo [14, 15, 17].…”

Bioenergetic adaptations in chemo-resistant ovarian cancer cells

“…Glycolysis is also a source of various macromolecules that are used by cancer cells for the synthesis of essential cell components such as proteins, nucleotides and lipids, and would enable them to proliferate rapidly 7 . In fact, glycolytic cancer cells, including ovarian, have been shown to be more invasive and metastatic [42][43][44] . We found that basal glycolysis rates significantly correlated with increased proliferation rates, indicating that cells that proliferated faster used more glycolysis.…”