Abstract
Energy metabolism has always been a hot topic in cancer progression and targeted therapy, and exploring the role of genes in energy metabolic pathways in cancer cells has become key to address this issue. Eukaryotic translation initiation factor 2α kinase 2 (EIF2AK2) plays regulatory roles in cancer and disorders of energy metabolism. Indeed, the role of EIF2AK2 in energy metabolism has been underestimated. The aim of this study is to reveal the expression specificity of EIF2AK2 in gastric cancer (GC) progression and metastasis, and to demonstrate the role of EIF2AK2 in energy metabolism, cytoskeleton, proliferation, death and metastasis pathways in GC cells. Mechanistically, EIF2AK2 overexpression promoted cytoskeleton remodeling and ATP production, mediated cell proliferation and metastasis, upregulated OAS1 expression, decreases p-AMPK expression and inhibited apoptosis in GC cells. Conversely, knockdown of EIF2AK2 resulted in the opposite effect. However, overexpression of OAS1 mediated the upregulation of mitochondrial membrane potential and promoted ATP production and NAD+/NADH ratio, but knockdown of OAS1 inhibited the above effects. In addition, knockdown of OAS1 had no effect on EIF2AK2 expression, but inhibited AMPK and upregulated p-AMPK expression. In conclusion, our study identified EIF2AK2 and OAS1 as previously undescribed regulators of energy metabolism in GC cells. We hypothesized that EIF2AK2-OAS1 axis may regulate energy metabolism and inhibit cellular malignant behavior in cancer cells by affecting ATP production to induce AMPK phosphorylation, suggesting EIF2AK2 as a potential therapeutic target for cancer cell progression.
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This study was supported by the Ordos Science and Technology Cooperation Fund, Project of Hebei Medical Science Research (No. 20221526).
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All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by [Yafang Lai], [**aofei, Wang], [**grong Ma], [Chaoqun Du], [Yuyu Wang], [Yaxin Wang], [Mingwei Zhao] and [Wenzhao Yuan]. The first draft of the manuscript was written by [Yafang Lai], [**aofei, Wang], [**grong Ma] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Lai, Y., Wang, X., Ma, J. et al. Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells. J Bioenerg Biomembr 56, 433–449 (2024). https://doi.org/10.1007/s10863-024-10023-0
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DOI: https://doi.org/10.1007/s10863-024-10023-0