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Published on: May 1, 2020
The role of Ephexin1 in translation and mTOR-targeted cancer therapy
Jeeho Kim1,2, In-Youb Chang3, Jung-Hee Lee1,4
1Laboratory of Genomic Instability and Cancer therapeutics, Chosun University School of Medicine, Gwangju, South Korea.
Abstract:
Ephexin1, also known as neuronal guanine nucleotide exchange factor (NGEF), plays a key role in axon guidance and synaptic homeostasis. However, our recent studies have revealed a critical role for Ephexin1 in the pathogenesis of colon and lung cancers. Here we used multidisciplinary approaches to further explore the underlying mechanisms of Ephexin1 in cancer progression. We discovered that Ephexin1 is essential for promoting polysome formation by coordinating the assembly of translation initiation complexes. Our investigations into gene expression affected by Ephexin1 deficiency showed that Ephexin1 specifically promotes the translation of genes containing 5'-terminal oligopyrimidine (TOP) or 5'-TOP-like motifs, identifying Ephexin1 as a key mediator of mTOR-regulated translation. Importantly, we found that the efficacy of mTOR inhibitors in treating lung cancer was significantly enhanced in a mouse xenograft model when Ephexin1 was deficient. This suggests that Ephexin1 could serve as a synthetic lethality target for mTORC1-targeting therapeutics in cancer treatment. Our findings provide mechanistic insights into the role of Ephexin1 in cancer pathogenesis and highlight its potential as a therapeutic target for improving current cancer treatment strategies.
Insights
Ephexin1 promotes cancer progression by enhancing protein translation, particularly for genes with specific 5' motifs. Targeting Ephexin1 could improve mTOR inhibitor efficacy in lung cancer treatment.
Area of Science:
- Molecular Biology
- Oncology
- Cancer Research
Background:
- Ephexin1 (neuronal guanine nucleotide exchange factor, NGEF) is crucial for neuronal development.
- Recent findings indicate Ephexin1's significant involvement in colon and lung cancer pathogenesis.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Ephexin1 drives cancer progression.
- To investigate Ephexin1's role in protein translation and its connection to cancer-related signaling pathways.
Main Methods:
- Multidisciplinary approaches including molecular biology techniques and gene expression analysis.
- Investigation of polysome formation and translation initiation complex assembly.
- Utilized a mouse xenograft model to assess therapeutic efficacy.
Main Results:
- Ephexin1 is essential for polysome formation and translation initiation complex assembly.
- Ephexin1 specifically enhances the translation of genes with 5 acronym{'-'}terminal oligopyrimidine (TOP) or 5 acronym{'-'}TOP-like motifs.
- Ephexin1 acts as a key mediator of mTOR-regulated translation.
- Deficiency of Ephexin1 significantly potentiated the efficacy of mTOR inhibitors in a lung cancer xenograft model.
Conclusions:
- Ephexin1 plays a critical role in cancer progression by regulating translation of specific mRNA motifs via the mTOR pathway.
- Ephexin1 represents a potential synthetic lethality target for mTORC1-targeting cancer therapeutics.
- Targeting Ephexin1 could offer a novel strategy to enhance current cancer treatment outcomes.
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