Of the origin of the Warburg effect and Cancer Dialysis
Author: Sture Hobro
Even though the consequences of the Warburg effect (overutilization of glucose also in the presence of oxygen) have been meticulously researched, and it has been more than 100 years since it was first described, the fundamental cause of the Warburg effect in cancer seems to be a mystery. We will describe our view of the most probable cause for this effect to arise.
Today the most common hypothesis is that the effect occurs as a response to mutations in oncogenes and tumor suppressor genes are thought to be responsible for malignant transformation, and the Warburg effect is considered to be a result of these mutations rather than a cause.
It is well known that mitochondria in cancer cells are deformed and dysfunctional. Two very basic functions in both cancer and healthy cells are to regulate ATP levels and oxidative balance inside the cell.
Therefor a second hypothesis suggest that the Warburg effect is a result of the mitochondria being unable to keep up with the energy demands of the cell and the cell must convert to anaerobic metabolism.
We suggest, as a third hypothesis, that the Warburg effect is mainly caused by a shift in the ratio between Reactive Oxygen Species (ROS) and ATP (energy) out from the ETC in the mitochondria. This leads to a need to upregulate glycolysis to cope with the increased oxidative stress and an increased ATP generation from the glycolysis.
However, if mitochondria and the ETC process are compromised as in cancer cells, more ROS and less ATP are produced from the ETC process, and the control of glycolysis will be disconnected from ATP production in the ETC process. Instead, a secondary control system becomes important, and increased ROS from the compromised ETC increases the need for glycolysis intermediates to produce NADPH to control increased ROS (mostly coming from compromised ETC). Secondly, reduced production from the compromised ETC leads to an increased need for ATP that further increases glycolysis.
During #Cancerdialysis, pronounced ketogenic conditions lead to a shortage of glucose and an increased need for ATP from ETC. In cancer cells, this leads to increased ROS from the compromised ETC and an increased need for glucose intermediates. In short, an unmanageable situation arises.
The figure depicts the Warburg control system as we imagine it and how increased ROS from compromised ETC drives a need first for glycolysis intermediates to produce antioxidants and secondly, from reduced outputs of ATP from ETC leads to a further increase in glucose needs.
