Oxidative Stress Stimulates P38 MAPK-Mediated Tumor Suppression

A new study finds that p38-alpha MAPK can sense oxidative stress in cells and respond by inhibiting tumor formation. The research, published in the February issue of the journal Cancer Cell, published by Cell Press, provides exciting new insight into the specific mechanisms by which ГЎ suppresses the development of cancer and identifies possible targets for development of new anticancer therapeutics.

The MAPK p38-alpha is a signaling protein that plays a critical role in coordinating cellular responses to stress, including oxidative stress that is characterized by the accumulation of increased levels of reactive oxygen species (ROS) within the cell. Although the p38-alpha pathway has been implicated in tumor suppression, the mechanisms involved are not well understood. Dr. Angel R. Nebreda from CNIO (Spanish National Cancer Center) in Madrid and colleagues induced malignant transformation in cells from mice lacking p38-alpha and in wild-type cells to study the importance of p38-alpha in tumorigenesis.

The deficiency of p38-alpha caused increased cell proliferation, decreased cell death via apoptosis, and enhancement of other characteristics associated with malignancy. Importantly, reintroduction of p38-alpha to the deficient cells reversed this phenotype. The researchers observed that the transformed cells lacking p38-alpha had much higher ROS levels than the wild-type cells. Further, ROS-stimulated p38-alpha activity in the wild-type cells stimulated apoptosis, whereas the cells lacking p38-alpha were resistant to ROS-induced apoptosis. The researchers point out that this finding may have clinical significance, as they observed that increased ROS levels were also linked to tumorigenic potential in several human cancer cell lines that were examined.

The authors suggest that it may be possible for cancer cells to escape the tumor-suppressive functions of p38-alpha by desensitizing p38-alpha to oxidative stress. Indeed, many tumor cells exhibit increased expression of GST proteins that are known to specifically inhibit p38-alpha activation by ROS. Reduced expression of GST in cancer cells correlated with increased p38-alpha activity and apoptosis, while enhanced expression of GST led to reduced p38-alpha activation, higher ROS levels, and enhanced malignancy of cancer cells.

Taken together, the findings suggest that p38-alpha plays a critical role in the negative regulation of tumor formation by triggering apoptosis in response to oncogene-induced ROS accumulation and that cancer cells may elude this protective mechanism by uncoupling ROS from p38-alpha. "Our results illustrate a mechanism used by cancer cells for the inactivation of tumor suppressor pathways and suggest that restoring the ROS-induced activation of p38 MAPK, for example, by targeting GST proteins, may be of potential therapeutic interest," concludes Dr. Nebreda.

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The researchers include Ignacio Dolado of CNIO (Spanish National Cancer Center) in Madrid, Spain and EMBL in Heidelberg, Germany; Aneta Swat and Nuria Ajenjo of CNIO (Spanish National Cancer Center) in Madrid, Spain; Gabriella De Vita of CEINGE in Naples, Italy; Ana Cuadrado and Angel R. Nebreda of CNIO (Spanish National Cancer Center) in Madrid, Spain.

This work was supported by pre-doctoral fellowships from EMBL and the Spanish Ministerio de Educacion y Ciencia as well as grants from Ministerio de Educacion y Ciencia and the FundaciГіn CientГ­fica de la AECC (Spain).

Dolado et al.: "p38-alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis." Publishing in Cancer Cell 11, 191-205, February 2007. DOI 10.1016/j.ccr.2006.12.013 http://www.cancercell.org

Contact: Erin Doonan
Cell Press