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Colorectal cancer: the two faces of p38 could MAP the way to new therapies
Colorectal cancer now ranks second in causing cancer deaths globally. New research from researchers in the Institute for Research in Biomedicine (IRB) in Barcelona suggests that an enzyme called p38, part of the MAP kinase family of proteins, has a dual role in colorectal cancer that could be exploited in future combination therapies. On the one hand, p38 contributes to intestinal barrier integrity, helping to keep out toxins and pathogens that could contribute to inflammation and tumour formation. On the other hand, once tumours have developed, p38 contributes to their growth and proliferation. The study is published online this week in the journal Cancer Cell.

MAP kinases are involved in relaying messages from outside the cell to the inside, thereby instructing the cell to make key decisions by controlling the activation or switching off of other proteins. P38 is a member of this family expressed in all cells of the body but with diverse functions depending on location or disease state. One of the roles of p38 is in inflammatory responses. It is well accepted that gastrointestinal inflammatory conditions such as Crohn’s disease is associated with increased risk of colorectal cancer. This link between inflammation and colorectal cancer prompted interest in dissecting the role of p38.

In the study, the researchers created mouse models of colorectal cancer and gastrointestinal inflammation. In one set of experiments, p38 gene expression was knocked down in epithelial cells forming the intestinal barrier and then the mice were subjected to tumour-inducing treatments. The mice that lacked p38 developed double the number of tumours than the p38-expressing mice. This indicates a crucial role for p38 in maintenance of the integrity of the gastrointestinal barrier which is protective against agents such as toxins and pathogens. This would be protective against tumour development.

However, in another arm of the study, the researchers studied mice that already had tumours and found another face of p38. They administered a p38 inhibitor to some mice and compared them to untreated mice. In the mice treated with p38 inhibitor, the tumours became substantially smaller. This suggests that in a scenario where cancer has developed, p38 contributes to tumour growth and proliferation.

The tumour-reducing capacity of p38 could be exploited in therapies for colorectal cancer but the use would have to be balanced by mindfulness of the protective role of p38 on intestinal barriers. Dr Angel R. Nebreda, senior author on the paper said: "p38 inhibitors may have clinical applications, but probably—and this forms part of the medicine of the future—these will be in combination with other drugs. We are trying to find out what p38 inhibitors should be combined with to make the tumour, which is now smaller, finally disappear." Meanwhile first author Dr Jalaj Gupta cautions: "Our study highlights the complexity of p38 functions, both in cancer and in the normal maintenance of tissues, and shows why an inhibitor of this molecule could effectively have undesirable side effects. This is why it is necessary to study in depth the patients and contexts in which treatment with such inhibitors would be suitable."

The two faces of p38 need to be considered in application to therapies in the future but the molecule shows promise as an effective target for reducing tumour size in preparation for surgical removal of tumours.


Dual function of p38alpha MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Jalaj Gupta, Ivan del Barco Barrantes, Ana Igea, Stratigoula Sakellariou, Ioannis S. Pateras, Vassilis G. Gorgoulis and Angel R. Nebreda. Cancer Cell (2014)

Press release: Institute for Research in Biomedicine (IRB Barcelona), available at:
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