Mnk earmarks eIF4E for cancer therapy.
نویسنده
چکیده
T he PI3K/Akt/mTORC1 axis is perhaps the most frequently activated pathway in human cancers. Therefore, concerted efforts are being made to inhibit this pathway pharmacologically for cancer therapy. Although some success has been achieved, the multiple feedback loops that “litter” this pathway (ref. 1; Fig. 1), combined with the potential toxicity resulting from its inhibition, make the pharmacological targeting efforts very challenging. The ideal goal is to inhibit the functionality of the pathway in cancer cells without affecting normal cells and without eliciting feedback loops that could diminish the therapeutic efficacy. Back-to-back papers published in PNAS may provide this kind of therapeutic avenue (2, 3). Previous studies suggest that the most critical target of the serine/threonine kinase Akt, required for tumorigenesis, is mTORC1 (4). The two major downstream targets of mTORC1 are S6K1 and eukaryotic initiation factor-4E binding proteins (4E-BPs), which regulate ribosomal biogenesis and mRNA translation. S6K1 is phosphorylated and activated by mTORC1, whereas 4E-BPs are phosphorylated and inactivated by mTORC1. The 4E-BPs bind to, and sequester, the eukaryotic initiation factor-4E (eIF4E), but their phosphorylation by mTORC1 induces their dissociation from eIF4E. The binding of eIF4E to the 4E-BPs prevents its interaction with the scaffold protein eIF4G, precluding the initiation of mRNA translation (ref. 5; Fig. 1). Thus, the phosphorylation of 4E-BPs by mTORC1 may constitute a rate-limiting step in mRNA translation. eIF4E is required for 5′-cap-dependent mRNA translation in general and for the translation of mRNAs with long and structured 5′ untranslated region (UTR) in particular (Fig. 1). Efforts to determine which of the two major downstream effectors of mTORC1, S6K1 or 4E-BPs, has the predominant role in cell proliferation and tumorigenesis show that it is likely the 4E-BPs (6), implying that the activity of eIF4E is the major determinant of mTORC1 tumorigenic activity. Supporting a major prooncogenic role of eIF4E are observations that it can contribute to the oncogenic transformation both in vitro and in vivo and that it is highly expressed in diverse types of cancer (reviewed in ref. 5). Collectively, the results imply that targeting eIF4E should have a major impact on the ability of the PI3K/ Akt/mTORC1 pathway to maintain cancer cells. But how would it be possible to inhibit eIF4E without introducing any toxicity? Fortunately, eIF4E is posttranslationally modified by phosphorylation, and this phosphorylation is important for its tumorigenic activity. The kinases that phosphorylate eIF4E on a conserved serine 209 are MAP kinase-interacting kinases, Mnk1 and Mnk2, which are activated by Erk and p38 (reviewed in ref. 7). Because Mnk is using eIF4G as a docking site to facilitate eIF4E phosphorylation (8), the phosphorylation of eIF4E by Mnk is apparently occurring after eIF4E-eIF4G binding and in concert with the assembly of the eIF4F complex (Fig. 1). The requirement of Mnk for Drosophila development underscores the importance of this phosphorylation for the function of eIF4E (9). Surprisingly, however, mice that lack both Mnk1 and Mnk2 do not have any apparent phenotype (11), which may cast doubt on whether phosphorylation by Mnk has any impact on the functionality of the mammalian eIF4E (7). Nevertheless, the phosphorylation of eIF4E by Mnk on Ser-209 is critical for the oncogenic activity of eIF4E (10). The most straightforward interpretation is that in mammalian cells, Ser-209 phosphorylation is not essential for the activity of eIF4E in normal cells but is required in cancer cells. Thus, targeting Mnks could be the ideal therapeutic approach that selectively affects cancer cells, and not normal cells, without toxicity. As a proof of concept of this possibility, Ueda et al. crossed mice lacking Mnk1 and Mnk2 with mice deficient in Pten, specifically in T cells (3). Pten loss in T cells induces early onset of T-cell lymphoma and with no tumor-free survival after 125 days. The deletion of Mnk1 and Mnk2 significantly and markedly decreased tumor incidence and increased tumor free survival. All of the lymphomas had high eIF4E expression and phosphorylation in comparison with normal thymocytes, but the phosphorylation of eIF4E was completely abolished in the absence of Mnk1 and Mnk2. Because human glioblastoma is one tumor type in which the PI3K/Akt/mTORC1 axis is frequently activated through the loss of Pten, Ueda et al. knocked down Mnk1 in glioblastoma cells and subjected them to xenografts assay. The knockdown of Mnk1 was sufficient to diminish the high level of Fig. 1. Schematic illustration depicting the cellular pathways that lead to eIF4E activation and phosphorylation byMnk1/2. The PI3K/Akt/mTORC1 pathway, which is frequently activated in human cancers, releases 4E-BPs from eIF4E, andenables eIF4E tobindeIF4G,which, in turn, assembles the eIF4F complex comprisingeIF4E, eIF4G, eIF4A, andeIF3.Mnk1andMnk2,whichareactivatedbyErkandby the stress induciblekinasep38,useeIF4Gasadocking site to phosphorylate efficiently eIF4E. The phosphorylation of eIF4E is critical for its oncogenic activity, probably through the differential translation of proteins that are required for oncogenesis. The phosphorylation of eIF4E byMnk1/2 provides a new avenue for cancer therapy. The inhibition of eIF4E phosphorylation could have similar consequences as the inhibitionmTORC1 by rapalaogs, butwith the advantage that it does not elicit the activation of Akt as a result of the inhibition of the negative feedback loops mediated bymTORC1.
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ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 107 32 شماره
صفحات -
تاریخ انتشار 2010