Many proteins have multiple roles. Often, the key to effective therapy is specificity. Not only does the treatment need to be specific for a particular physiological target, often a protein, but the therapeutic effects involve only a single function or subset of the target’s functions or needs to affect the target only within a specific physiological context. Therapies that affect other molecular targets or that affect the beneficial roles of a specific target can have adverse effects or unintended consequences. However, developing medications and therapeutic strategies that are so selective is a major challenge in pharmacology and drug development.
Maik-Rachline and colleagues devise a strategy to specifically inhibit the activity of the enzymes p38 and JNK, two enzymes involved in the inflammatory response, in the nucleus without affecting the activity of these enzymes in the cytosol. Inflammation plays a critical role in the response to infection and injury. However, chronic inflammation can cause tissue damage and contribute to the development and progression of cancer. JNK and p38 are protein kinases, which are enzymes that add phosphate groups onto proteins to regulate protein function. Like most protein kinases, p38 and JNK phosphorylate many different proteins and function in multiple parts of the cell. Whereas complete inhibition of the activity of these kinases may have undesired effects, inhibition of their activity in a specific subcellular location may prove a better option.
JNK and p38 (for which there are each 2 isoforms) are active in the cytosol and the nucleus. Their entry into the nucleus involves the formation of complexes with importins (Imps), either an Imp3-Imp9 complex or an Imp3-Imp7 complex. Maik-Rachline and colleagues identified the site that mediated the interaction between the Imp complex and these kinases. Using this information, they designed a peptide that interfered with that interaction and thus prevented the translocation of both JNK and p38 into nucleus. With this strategy, the cytosolic activity of these enzymes was retained, while the nuclear activity was impaired (Figure 1). The peptide inhibited the proliferation of some cancer cell lines in culture as effectively, or in some cases more effectively, than an inhibitor of the kinase activity of p38. Using one of the cell lines that could be inhibited by the peptide, the authors established tumors in mice. Injection of the peptide into or administration of a p38 inhibitor to mice reduced the size of the tumors.
Several types of cancer, including colon and pancreatic, are associated with inflammation and cell stress. The authors tested the effectiveness of the peptide in a mouse colon cancer model related to inflammation. Not only did treatment with the peptide preserve colon health, reducing pathological weight loss, colitis, diarrhea, loss of colon length, and inflammation; it also reduced colitis-associated tumor formation and growth. Intriguingly, the beneficial effect appeared related to the inhibition of the nuclear translocation of p38 in macrophages in the colon, thus, providing evidence that altered function of these immune cells is a contributing factor in colon cancer.
This study shows that an approach to selective inhibition of the activity of an enzyme is to block access to its targets by preventing the transport of the enzyme into a subcellular compartment. This strategy represents a drug development alternative to inhibiting the catalytic site of an enzyme.
G. Maik-Rachline, E. Zehorai, T. Hanoch, J. Blenis, R. Seger, The nuclear translocation of
the kinases p38 and JNK promotes inflammation-induced cancer. Sci. Signal. 11, eaao3428 (2018). PubMed
Cite as: N. R. Gough, Blocking Nuclear Translocation to Treat Cancer and Colitis. BioSerendipity (16 April 2018) www.bioserendipity.com/blocking-nuclear-translocation-to-treat-cancer-and-colitis.