A study published in the journal eLife, explains how tumor cells can grow in conditions of low oxygen, and discloses a new and unique drug targets that can be used for future cancer therapies.
Hypoxia - lack of oxygen in the tissues of the body - it is a known cancer indication. "We know that the hypoxic part of tumors containing fat droplets, and the data indicate that the ability of tumors to accumulate these drops is related to its ability to survive in conditions of low oxygen," explains Xiaodong Zhang, Ph.D., a researcher at the University of Arizona Mayo, USA, and lead author of the study. "But we do not understand how and why these lipid droplets are formed, so we began to study it."
The team is particularly interested in the role of an enzyme molecule called adipose triglyceride lipase (ATGL), because it accelerates the decomposition of fat and demonstrates the suppression of tumor growth. But when they destroyed ATGL gene in hypoxic cancer cells, they did not observe further accumulation of droplets, suggesting a change ATGL activity, which caused a reduction in body fat.
To learn more, they searched for other protein molecules that could participate in ATGL activity. This led them to a molecule called HIG2, which is abundantly present in a wide variety of solid tumors, including colon cancer and kidney. They found that HIG2 was co-located with ATGL and has similar properties to another molecule that blocks ATGL. They tested the effects on ATGL HIG2 and found that first molecule specifically blocks fat breakdown caused ATGL, and as a result, increases the size of the fat droplets in the cells.
The team then wanted to see whether these effects are replicated in cells with low oxygen content. I would like to HIG2 was dramatically activated in conditions of low oxygen and caused an increase in the accumulation of fat droplets in the cells. Again, with the mutated HIG2 cells did not show any of these effects. However, when ATGL mutated, the accumulation of fat recovered. This proves that HIG2 works for larger, fat storage and reduction in the cell metabolism by a specific blocking ATGL.
So why hypoxic cancer cells try to block fat breakdown? The following experiments the team showed that cells without HIG2 conditions with low oxygen content leads to excessive production of reactive oxygen species - an increase of nearly 250%. In mice with tumors removal HIG2 caused profound delay in tumor growth compared to mice with a functioning HIG2.
"We have found an important survival mechanism that cancer cells use when under low-oxygen", - concludes the senior author Jun Liu, a professor of biochemistry and molecular biology at the campus of the Mayo Clinic in Arizona. "Our results warrant further investigation of the interaction HIG2-ATGL as the main therapeutic strategy for the treatment of a wide range of aggressive cancers."