The Nuclear Translocation of p38 and JNK as a Therapeutic Target for Cancer and Inflammation-Induced Diseases.

The stimulated nuclear translocation of signaling proteins, such as MAPKs, is a necessity for the initiation and regulation of their physiological functions. Previously, we elucidated the mechanism of nuclear translocation of either p38 or JNK MAPKs, and showed that it involves binding to either importin7 or importin9 in a dimer with importin3. Here, we identified the binding site of p38 and JNK to importin7 and importin9, and developed a myristoylated peptide based on the binding site of p38 to the importins, which we termed the PERY peptide. This peptide specifically blocked the interaction of p38 and JNK with importin7 and 9, restricted their nuclear translocation and inhibited phosphorylation of their nuclear substrates. These effects resulted in reduced proliferation of several breast and melanoma cancer cell lines in culture and the growth of a human breast cancer xenograft in mice, but did not affect the proliferation of various other cancer cell lines. Additionally, the PERY peptide significantly inhibited inflammation in mice, as manifested in models of DSS-induced colitis and colitis-associated colon cancer. Moreover, in the AOM/DSS colitis-associated colon cancer model, systemic PERY peptide administration prevented colon cancer, even better than a commercial p38 inhibitor. The in vivo analysis further suggested that this effect was mediated by PERY peptide-induced prevention of the nuclear translocation of p38 in macrophages. Together, these results support the use of the nuclear translocation of p38 and JNK as a novel drug target to treat various cancers and inflammation-induced diseases.