Abstract
The eukaryotic initiation factor eIF4E is essential for cap-dependent initiation of translation in eukaryotes. Abnormal regulation of eIF4E has been implicated in oncogenic transformation. We developed an eIF4E-binding peptide derived from Angel1, a partner of eIF4E that we recently identified. We show here that this peptide fused to a penetratin motif causes drastic and rapid cell death in several epithelial cancer cell lines. This necrotic cell death was characterized by a drop in ATP levels with F-actin network injury being a key step in extensive plasma membrane blebbing and membrane permeabilization. This synthetic eIF4E-binding peptide provides a candidate pharmacophore for a promising new cancer therapy strategy.
Highlights
EIF4E is regulated at multiple levels, including through interactions with a family of eIF4E-binding proteins that compete with eIF4G to bind to the dorsal face of eIF4E
Upon mitogen activation or stimulation with growth factors or cytokines, 4E-BP1 is phosphorylated at multiple sites by the mammalian target of rapamycin signaling pathway leading to its dissociation from eIF4E.5
An 11 amino acid sequence derived from the recognition motif of Angel[1] was fused to the yellow fluorescent protein (YFP) as a carrier
Summary
EIF4E is regulated at multiple levels, including through interactions with a family of eIF4E-binding proteins that compete with eIF4G to bind to the dorsal face of eIF4E. EIF4E activity has been linked to growth stimulation and oncogenic transformation that enhance the translation of a subset of mRNAs believed to be poorly expressed in normal cellular conditions. These mRNAs predominantly encode growth factors and proto-oncogenes involved in cell proliferation and promote tumor cell survival, angiogenesis, transformation, invasion and metastasis.[6]. Interacting peptide designed from the eIF4E-binding motif of Angel[1] to target eIF4E–eIF4G interactions We demonstrate that this peptide can efficiently inhibit in vitro translation. It induces rapid cell death in a wide variety of cancer cell lines involving a dramatic disorganization of the F-actin network, cell blebbing and plasma membrane rupture
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