Thrombin is a key protease involved in blood coagulation, complement activation, inflammation, angiogenesis, and tumor invasion. Although induced in many (patho-)physiological conditions, the underlying mechanisms controlling prothrombin expression remained enigmatic.
Presented in the journal Molecular Cell, a new study provides insight how prothrombin expression is regulated by a posttranscriptional regulatory mechanism in response to stress and inflammation. Researchers from the Molecular Medicine Partnership Unit (MMPU), a partnership launched in 2002 between the European Molecular Biology Laboratory (EMBL) and the University of Heidelberg Medical Centre in Germany, wrote their findings might explain the enigmatic relationship between enhanced pro-coagulation activities and the outcome of cancer and could be used to develop novel ways to treat various disorders.
Patients suffering from cancer are at a higher risk of blood hypercoagulation. This was first described by French physician Armand Trousseau in the 19th century. Doctors have recently determined that people with activated blood coagulation have a higher chance of developing cancer than those who don’t. Also, recent studies revealed that anti-coagulants could fight and prevent cancer. But no one had found the connection between cancer progression and blood clots. This is where the German researchers entered the picture.
The amount of thrombin produced by the body’s cells is determined by two types of protein: proteins that accelerate production and proteins that slow it down. The both types act by binding to the cellular machinery that synthesises thrombin. In normal cases, thrombin levels are kept low by production-slowing proteins.
The latest study found that another protein, p38 MAPK (Mitogen-activated protein kinase), kicks into action when cells are under stress from inflammation. p38 MAPK adds a chemical tag to the slow-producing proteins. The result was that the production-slowing proteins had a hard time to bind to the thrombin-synthesising machinery. This enables the proteins that speed up production to take control.
Inflammation triggered by cancer could result in increased thrombin levels and, as thrombin is a coagulation agent, this could explain why cancer patients have a higher risk of suffering from hypercoagulation. p38 MAPK upmodulates canonical 3 end processing components and this novel mechanism emerges as a key mechanism of gene regulation with broad biological and medical implications. According to Matthias Hentze, Associate Director of EMBL and co-Director of MMPU, knowing the exact molecules involved, and how they act, has implications for treatment, especially as drugs that inhibit p38 MAPK are already being tested in clinical studies for other conditions.
Besides its influence as a coagulation agent, thrombin helps the development of new blood vessels and can degrade the extracellular matrix that keeps cells together. According to the German research team, there is a chance that the cancer cells are boosting thrombin production to help the tumor spread, by making it easier to invade healthy tissue and creating blood vessels to supply the new tumor cells. This could be the reason people with hypercoagulation problems are more likely to develop cancer.
For more information:
Danckwardt S, Gantzert AS, Macher-Goeppinger S, Probst HC, Gentzel M, et al. p38 MAPK Controls Prothrombin Expression by Regulated RNA 3′ End Processing.Mol Cell. 2011 Feb 4;41(3):298-310