Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
The Ella Lemelbaum Institute for Melanoma, The Sheba Medical Center, Ramat Gan, and the Department of Clinical Microbiology and Immunology, Tel Aviv University, Tel Aviv 52621, Israel.
Nat Commun. 2015 Mar 30;6:6685. doi: 10.1038/ncomms7685.
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.
ERK1/2 功能的一个标志是其核易位，这主要是增殖诱导所必需的。留在细胞质中的激活的 ERK1/2 分子会启动其他活动，包括即时反馈环。因此，核易位的阻止应该抑制增殖，而不影响细胞质诱导的细胞过程。在这里，我们提出了一种源自 NTS 的豆蔻酰化磷酸模拟肽，它可以阻断 importin7 和 ERK1/2 的相互作用，从而阻止后者的核易位。在培养物中，该肽诱导黑素瘤细胞凋亡，抑制其他癌细胞的活力，但对非转化、永生化细胞没有影响。它甚至抑制了 PLX4032 和 U0126 耐药黑素瘤细胞的活力。在异种移植模型中，该肽抑制多种癌症，并且在预防黑素瘤复发方面的作用明显优于 PLX4032。本研究为将 ERK1/2 的核易位作为治疗各种与 ERK1/2 相关癌症的药物靶点提供了概念验证。
