Tuesday, August 5, 2014

It's a TRAP: a new target in the fight against cancer discovered

By studying a protein that is key to tumor metabolism, researchers have discovered its role in a number of age-related pathologies, including obesity, oxidative stress, and spontaneous tumor formation.  This protein, TRAP-1 (TNFR-associated protein-1), is a chaperone protein belonging to the Hsp90 family.  These proteins maintain cellular processes, including protecting against oxidative stress and apoptosis.  Chaperone proteins are highly expressed in cancer cells, partly explaining their resilience.  In healthy cells, TRAP-1 is normally involved in maintaining mitochondrial integrity, and protecting against oxidative stress.  Cancer cells rewire cellular energy production in the mitochondria, increasing levels of glycolysis and lactic acid fermentation, making TRAP-1 a potential target for anticancer strategies. 

Higher standardized uptake value (SUV) in the livers of mice lacking
TRAP-1 (right) indicates increased glucose consumption as a result
of glycolysis.
By generating mice lacking TRAP-1, the authors were able to show that this protein plays a key role in cellular metabolism.  When cells lose TRAP-1 function, proteins within the mitochondria are misfolded.  This causes cells to switch to alternative metabolic pathways, like glycolysis (a pathway that breaks down glucose to produce energy) and oxidative phosphorylation (a pathway that uses oxygen to produce cellular energy).  Other changes that occurred in cells lacking TRAP-1 included increased accumulation of other types of chaperone proteins, including other Hsp90 proteins, and slightly higher levels of reactive oxygen species (ROS), which cause oxidative stress and DNA damage.  This DNA damage allowed cells to slow growth in order to undergo natural DNA repair, which ultimately slowed aging, and was associated with overall increased health in older mice lacking TRAP-1, compared to their age-matched, normal littermates.  The TRAP-1 knock-out mice had lower incidences of age-related obesity, oxidative damage, and tumor formation, most likely as a result of decreased cell proliferation.

When TRAP-1 function was removed from cancer cells, the response was a catastrophic, causing metabolic problems that ultimately led to cell death.  That's because cancer cells have very high energy needs, and the compensatory metabolic pathways were unable to meet the increased energy demands.  Because TRAP-1 is important in both protecting cells and in oxidative phosphorylation, which is being increasingly recognized as a key ingredient in tumor proliferation, this protein has become an attractive therapeutic target in cancer cells.  What is especially promising about this study is that the adverse effect of removing TRAP-1 function only occurred in cancer cells - it seemed to have a protective effect in healthy cells.

A few weeks ago, I wrote about a very interesting use of evolutionary game theory to figure out when cancer cells are most vulnerable - which is during the switch in energy production.  What I find most remarkable about this study is that it provides a way to put this mathematical modeling into practice.  When TRAP-1 function is removed, cancer cells become more vulnerable to apoptosis.  Perhaps the key to fighting cancer may lie in the combination of both methods - in targeting TRAP-1 during critical transitions in cancer metabolisms to ensure efficient and effective treatment.  While the problem remains finding the therapeutic windows for cancer vulnerability, the authors have definitely strengthened the case for targeting the Hsp90 family in the development of cancer therapies.  They have also opened up a fascinating discussion on the implications of chaperone proteins in cellular metabolism and longevity.

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