Positive feedback between ROS and cis-axis of PIASx alpha/p38 alpha-SUMOylation/MK2 facilitates gastric cancer metastasis

MAPK/p38 is an important mammalian signaling cascade that responds to a variety of intracellular or extracellular stimuli, such as reactive oxygen species (ROS), and participates in numerous physiological and pathological processes. However, the biological function of p38 in different tumors, and even at different stages of the same tumor, remains elusive. To further understand the regulatory mechanism of p38 and oxidative stress in the occurrence and development of gastric cancer, we report SUMOylation as a novel post-translational modification occurring on lysine 152 of MAPK14/p38 alpha through immunoprecipitation and series of pull-down assays in vitro and in vivo. Importantly, we determine that p38 alpha-SUMOylation functions as an authentic sensor and accelerator of reactive oxygen species generation via interaction with and activation of MK2 in the nucleus, and the ROS accumulation, in turn, promotes the SUMOylation of p38 alpha by stabilizing the PIASx alpha protein. This precise regulatory mechanism is exploited by gastric cancer cells to create an internal environment for survival and, ultimately, metastasis. This study reveals novel insights into p38 alpha-SUMOylation and its association with the intracellular oxidative stress response, which is closely related to the processes of gastric cancer. Furthermore, the PIASx alpha/p38 alpha-SUMOylation/MK2 cis-axis may serve as a desirable therapeutic target in gastric cancer as targeting PIASx alpha, MK2, or a specific peptide region of p38 alpha may reconcile the aberrant oxidative stress response in gastric cancer cells.