The nuclear translocation of ERK1/2 as an anticancer target

Abstract

A hallmark of the ERK1/2 functioning is their nuclear translocation, which is mainly required for the induction of proliferation. Activated ERK1/2 molecules that remain in the cytoplasm initiate other activities, including immediate feedback loops. Prevention of the nuclear translocation should therefore inhibit proliferation, without affecting cytoplasm-induced cellular processes. Here we present an NTS-derived myristoylated phosphomimetic peptide, which blocks the interaction of importin7 and ERK1/2, and consequently the nuclear translocation of the latter. In culture, the peptide induces apoptosis of melanoma cells inhibits the viability of other cancer cells, but has no effect on non-transformed, immortalized cells. It even inhibits the viability of PLX4032-and U0126-resistant melanoma cells. In xenograft models, the peptide inhibits several cancers, and acts much better than PLX4032 in preventing melanoma recurrence. This study provides a proof of concept for using the nuclear translocation of ERK1/2 as a drug target for the combat of various ERK1/2-related cancers.

A novel arylbenzofuran induces cervical cancer cell apoptosis and G1/S arrest through ERK-mediated Cdk2/cyclin-A signaling pathway

“…ERK1/2 is activated through phosphorylation of activation-loop residues threonine (Thr) 202/tyrosine (Tyr) 204 and Thr 185/Tyr 187, respectively. Activated ERK1/2 translocates into nucleus and participates in the regulation of G1- to S-phase transition, and the nuclear translocation of ERK1/2 is served as an anticancer target [25, 26]. So, we want to clarify whether ERK-pathway was activated in G1/S-phase arrest induced by Ary.…”

Targeting RAS -mutant Cancers: Is ERK the Key?

“…In contrast, nonresponsive tissue was associated with cytoplasmic ERK [79] . Further, the nuclear import protein importin7 facilitates ERK nuclear translocation by recognition of the phosphorylated nuclear translocation signal (NTS), and an NTS-derived phosphomimetic peptide that blocks nuclear translocation of ERK impairs the growth of RAS - or BRAF -mutant tumor cell lines [80] . Because many nuclear ERK substrates are associated with cell proliferation, whereas ERK negative feedback targets are cytosolic (Figure 5), the selective inhibition of phosphorylation of ERK nuclear substrates might favor inhibition of tumor growth.…”

The Nuclear Translocation of Mitogen-Activated Protein Kinases: Molecular Mechanisms and Use as Novel Therapeutic Target

“…This combination provides a possible treatment for this disease, which currently does not have an effective treatment. We also showed that the EPE peptide effectively inhibits tumour growth in xenograft models of Ras and B-Raf-transformed cancers, and most importantly, we showed that this inhibitor is less vulnerable to development of resistance than the clinically used B-Raf inhibitor vemurafenib [126]. …”

“…Recently, our group undertook to prevent ERK1/2 nuclear translocation by preventing the interaction of ERK1/2 with its nuclear shuttling carrier importin7. We synthesized a myristoylated phosphomimetic peptide (EPE peptide) based on the interaction site of ERK1/2 with importin7 (NTS; [126]). This peptide was predicted to bind to importin7 and compete with the interaction of ERK1/2 with importin7, and consequently abolish the nuclear translocation of ERK1/2.…”