Biologists have long appreciated that cancer cells demonstrate abnormal metabolism of the simple sugar glucose, a phenomenon known as the Warburg effect. Recently, there has been renewed interest in the abnormal energy processing of cancer cells.
A team from the Hopkins medical school led by Chi V. Dang has revealed a novel mechanistic link between glucose metabolism and a cell-cycle protein known as c-Myc.
The researchers report in Nature that increased levels of c-Myc in cancer cells cause an increase in levels of glutaminase, a protein that helps cells convert the amino acid glutamine into an energy source. The breakdown of glutamine is therefore a new source of energy for cancer cells.
The upregulation, or increase in cellular levels, of glutaminase is mediated indirectly through the use of small nucleic acid molecules called micro-ribonucleic acids (miRNAs). Dang's team has worked out the way c-Myc regulates glutaminase.
This is a unique find for the researchers, showing a new pathway for an old protein. For some time, c-Myc has been known as an oncogene, or a gene that causes cancer when it is mutated. If c-Myc is altered so that it does not function normally, then normal cells can become cancerous.
Previous research has shown that c-Myc can enhance traditional cancer pathways including Wnt, sonic hedgehog and other growth pathways. One reason c-Myc has received so much attention lately is its involvement in stem cell research.
To understand this new pathway, the team from Hopkins induced increased amounts of c-Myc protein in cells and then looked at the corresponding expression of glutaminase protein.
Based on previous studies, the researchers believed there must be some intermediate that communicates between these two proteins, because they do not interact directly.
In an initial screen for proteins that are upregulated or down-regulated as c-Myc levels are increased, two miRNAs appeared as candidates. Upon further investigation, the team showed that the c-Myc protein interacts directly with the two miRNAs, trapping the molcules in a complex with other proteins.
Since the miRNAs are sequestered in this protein complex, they are unable to interact with glutaminase to stop its expression, thereby allowing the cells to become cancerous.
Using traditional methods as well as a new eye for something old, the researchers were able to unravel a new biochemical pathway and increase our knowledge of how cancer cells function. It is with this understanding that new ways of combating cancer will emerge, in the hope of curing some forms of cancer.
