Every single cell in our body needs energy to function, which is derived from the sugars we consume in our diet. Normal and healthy tissues in our body convert these sugar into lactate as a normal part of metabolism. Cancerous cells or tumors, on the other hand, are glucose guzzlers, and convert significantly higher amounts of sugar into lactate than healthy cells, a phenomenon termed as Warburg effect that has been hypothesized to be related to high growth rate of cancer cells.
As one of the most prominent features of cancer cells, this phenomenon has been extensively studied but thus far, it has been unclear whether the effect is merely a symptom of cancer, or a cause.
While earlier research into cancer cell metabolism focused on mapping out metabolic peculiarities, this new study has clarified how the Warburg effect stimulates tumor growth.
A nine-year joint research project conducted by VIB, KU Leuven and VUB has reported that high sugar metabolism in cells was associated with activation of Ras. Ras is a protein that controls cell proliferation and has been found to cause cancer when mutated.
The team found that yeast cells with cellular accumulation of fructose 1,6-bisphosphate, an intermediate in glucose metabolism, resulted in hyperactivation of Ras. In lay terms, the researchers found that the yeast that had an overactive influx of glucose caused the Ras proteins to activate too much, which would then allow the cells to grow at an accelerated rate.
“Our research reveals how the hyperactive sugar consumption of cancerous cells leads to a vicious cycle of continued stimulation of cancer development and growth,” said Johan Thevelein who led the study at KU Leuven, Belgium. He added, “Thus, it is able to explain the correlation between the strength of the Warburg effect and tumour aggressiveness. This link between sugar and cancer has sweeping consequences. Our results provide a foundation for future research in this domain, which can now be performed with a much more precise and relevant focus.”
Binding studies conducted by the team also confirmed that fructose 1,6-bisphosphate was involved in activation of Ras. Cultured human cells – normal as well as cancerous – showed activation of Ras upon increased glucose consumption. Interestingly though, activation of Ras was not associated with an increased proliferation rate.
Yeast cell research was essential to the discovery, as these cells contain the same ‘Ras’ proteins commonly found in tumor cells. Using yeast as a model organism, the research team examined the connection between Ras activity and the highly active sugar metabolism in yeast.
“We observed in yeast that sugar degradation is linked via the intermediate fructose 1,6-biophosphate to the activation of Ras proteins, which stimulate the multiplication of both yeast and cancer cells. It is striking that this mechanism has been conserved throughout the long evolution of yeast cell to human,” said Thevelein.
This study provides an in-depth understanding of how sugar influx is related to Ras activation in yeast as a model, for cancer cells. It may be noted, however, that Ras regulates several downstream signaling pathways, and its activation may result in different cellular outcomes depending on cell type and other factors. Moreover, the authors did not notice a change in growth of cells in presence of excess glucose, although Ras protein was activated.
The connection between increased sugar influx and cancer cell growth may be complex and possibly involves other proteins and signaling pathways.
The team’s research has been published in the journal Nature Communications.