Almost a hundred years, scientists have watched the strange behavior of cancer cells, known as the Warburg effect. It lies in the fact that the cancer cells are selected less efficient way to produce energy. While normal cells are used aerobic glycolysis to produce energy-36 molecules of adenosine triphosphate (ATP) with glucose, most cancer cells, despite the presence of oxygen, are switched to anaerobic glycolysis, at which produced only two ATP.
This process depends on the class of enzymes lactate dehydrogenase (LDH), the most important "player" is the lactate dehydrogenase A (LDGA). Inhibition LDGA can stop cancer cells generate energy necessary for the growth and survival of the tumor, but little is known about how effective it can be mainly due to the absence of pharmacological inhibitors.
Using genetic and pharmacological agents, scientists from the Medical Sanford Burnham Prebys Research Institute have found that blocking LDGA has a limited effect on melanoma cells, as they are able to redirect energy production. Results of studies have identified an alternative path of growth, caused by the molecule ATF4 and reveals potential new targets for drug development. The study was published in «EMBO» magazine.
"We decided to investigate what's really going on with the melanoma cells in inhibiting LDGA - the scientists noted. - We have identified a signaling pathway ATF4, which induces cancerous melanoma cells to collect the essential amino acids necessary to support the growth and survival of the tumor in response to inhibition of LDGA. We believe that targeting this pathway in combination with drugs aimed at LDGA may be a promising treatment for melanoma. "
Every year more than 9000 Americans die from melanoma skin cancer. Over the last decade personalized therapies aimed at modified proteins BRAF and MEK, which are characteristic of more than 50% of people with melanoma, patients have improved survival. But cancer cells can adapt to the treatment, causing relapse after remission.
"Drug resistance in patients developing very quickly - in just a few months after the start of treatment, which creates a need for new drugs," targets ", and therapeutic approaches" - the researchers reported.
ATP to amino acids
When you lock LDGA scientists have recorded a few changes in melanoma cells. These cells are switched from an ATP-generating aerobic glycolysis in the use of glutamine - an amino acid. The study authors found that ATF4 manage this process, encouraging greater uptake of amino acids by cells. Increasing the number of amino acids activated the master regulator of the growth of mTORC1, which allowed cancer cells to grow. Blocking both ldhA, mTORC1 and stop the growth of the cells, indicating that the therapeutic potential of targeting this pathway. The scientists also identified an additional "target", such as glutamine metabolism and transfer of MAPK signaling, targeting already established pharmacological inhibitors.
"When we examined tumor samples obtained from patients with drug-resistant melanoma, we discovered amazingly similar results. In cancer tissues increased metabolic signaling is associated with ATF4. This indicates that cancer cells use the same lifeline supported ATF4, to continue to grow. "
"Our study sheds light on the Warburg effect, helping to understand why cancer cells prefer inefficient way to stimulate its growth. We assume that the cancer cells are much in need of amino acids, in contrast to the ATP. Perhaps these fast growing cells the Warburg effect is considered more efficient to collect the protein building blocks "- noted isledovateli.
The results of the new work to help understand how to restrict access to amino acids affects the cancer cells at a molecular level. The new data may help to identify "weak spots" of cancer cells and potential therapeutic targets.