Research ArticleDRUG DEVELOPMENT

The nuclear translocation of the kinases p38 and JNK promotes inflammation-induced cancer

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Sci. Signal.  10 Apr 2018:
Vol. 11, Issue 525, eaao3428
DOI: 10.1126/scisignal.aao3428

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A peptide to treat inflammatory disease

Chronic inflammation promotes the development of tumors in various tissues, notably in the gastrointestinal tract. Inflammation induces proliferation and feedforward inflammatory cytokine production in cells typically through the kinases p38 and JNK, which are associated with various diseases. Maik-Rachline et al. developed a peptide that blocked the activities of p38 and JNK specifically in the nucleus. The peptide, called PERY, prevented the development of inflammation-associated colon cancer in mice. Furthermore, without detectable side effects, the peptide protected mice from chemical-induced colitis that models irritable bowel syndrome. These findings suggest that this peptide might be used to treat colitis in patients and prevent the development of colitis-induced colon cancer.

Abstract

The stimulated nuclear translocation of signaling proteins, such as MAPKs, is a necessity for the initiation and regulation of their physiological functions. Previously, we determined that nuclear translocation of the MAPKs p38 and JNK involves binding to heterodimers comprising importin 3 and either importin 7 or importin 9. Here, we identified the importin-binding region in p38 and JNK and developed a myristoylated peptide targeting this site that we called PERY. The PERY peptide specifically blocked the interaction of p38 and JNK with the importins, restricted their nuclear translocation, and inhibited phosphorylation of their nuclear (but not cytoplasmic) substrates. Through these effects, the PERY peptide reduced the proliferation of several (but not all) cancer cell lines in culture and inhibited the growth of a human breast cancer xenograft in mice. In addition, the PERY peptide substantially inhibited inflammation in mice, as manifested in models of colitis and colitis-associated colon cancer. The PERY peptide more effectively prevented colon cancer development than did a commercial p38 inhibitor. 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.

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