Prevention of ERK Nuclear Translocation Blocks Cancer Proliferation in Animal Models

The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase is transported to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. Dysregulation of this pathway has been implicated in some 85% of all cancer types.

Investigators at the Weizmann Institute of Science (Rehovot, Israel) explored a novel approach to cancer therapy based on prevention of the nuclear translocation of ERK1/2, which was expected to inhibit proliferation, without affecting cytoplasm-induced cellular processes. To this end they developed a myristoylated phosphomimetic peptide, which blocked the interaction of the importin7 transport protein and ERK1/2, and consequently the nuclear translocation of the latter.

Results published in the March 30, 2015, online edition of the journal Nature Communications revealed that in culture, the peptide induced apoptosis of melanoma cells, inhibited the viability of other cancer cells, but had no effect on non-transformed, immortalized cells. Furthermore, it inhibited the viability of PLX4032 and U0126 drug resistant melanoma cells. In xenograft models, the peptide inhibited several cancers, and acted much better than PLX4032 in preventing melanoma recurrence.

"In some of the cancers, the molecule worked even better in the animal models than it did in culture. The cancers disappeared within days and did not return," said senior author Dr. Rony Seger, professor of biological regulation at the Weizmann Institute of Science. "In addition, the fact that the molecules do not destroy the ERK but only stop it from entering the nucleus may be good news for healthy cells. Every pathway is associated with a different disease. The trick is to find the molecules that can selectively target just one stage in the process."

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Weizmann Institute of Science