Abstract
BackgroundThe Warburg phenotype in cancer cells has been long recognized, but there is still limited insight in the consecutive metabolic alterations that characterize its establishment. We obtained better understanding of the coupling between metabolism and malignant transformation by studying mouse embryonic fibroblast-derived cells with loss-of-senescence or H-RasV12/E1A-transformed phenotypes at different stages of oncogenic progression.ResultsSpontaneous immortalization or induction of senescence-bypass had only marginal effects on metabolic profiles and viability. In contrast, H-RasV12/E1A transformation initially caused a steep increase in oxygen consumption and superoxide production, accompanied by massive cell death. During prolonged culture in vitro, cell growth rate increased gradually, along with tumor forming potential in in vitro anchorage-independent growth assays and in vivo tumor formation assays in immuno-deficient mice. Notably, glucose-to-lactic acid flux increased with passage number, while cellular oxygen consumption decreased. This conversion in metabolic properties was associated with a change in mitochondrial NAD+/NADH redox, indicative of decreased mitochondrial tricarboxic acid cycle and OXPHOS activity.ConclusionThe high rate of oxidative metabolism in newly transformed cells is in marked contrast with the high glycolytic rate in cells in the later tumor stage. In our experimental system, with cells growing under ambient oxygen conditions in nutrient-rich media, the shift towards this Warburg phenotype occurred as a step-wise adaptation process associated with augmented tumorigenic capacity and improved survival characteristics of the transformed cells. We hypothesize that early-transformed cells, which potentially serve as founders for new tumor masses may escape therapies aimed at metabolic inhibition of tumors with a fully developed Warburg phenotype.
Highlights
The Warburg phenotype in cancer cells has been long recognized, but there is still limited insight in the consecutive metabolic alterations that characterize its establishment
This metabolic phenotype is characterized by a shift from oxidative phosphorylation (OXPHOS) towards aerobic glycolysis as the main source of ATP production, a phenomenon first described by Otto Warburg [2]
The question why tumor cells have a relatively high glycolytic rate compared to OXPHOS activity goes well beyond the basics of which of the two processes is more efficient in terms of ATP production
Summary
The Warburg phenotype in cancer cells has been long recognized, but there is still limited insight in the consecutive metabolic alterations that characterize its establishment. Growth and viability of malignant cells is strongly dependent on their ability to adopt an altered metabolic profile that fulfills the synthetic and bioenergetic requirements for fast and uncontrolled growth. This metabolic phenotype is characterized by a shift from oxidative phosphorylation (OXPHOS) towards aerobic glycolysis as the main source of ATP production, a phenomenon first described by Otto Warburg [2]. The increased dependency of cancer cells on aerobic glycolysis is a well-recognized hallmark [3], but still relatively little is known about the factors that are in control during the early phases of the transformation process. The question why tumor cells have a relatively high glycolytic rate compared to OXPHOS activity goes well beyond the basics of which of the two processes is more efficient in terms of ATP production
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