Knockdown of EIF2AK2-OAS1 axis reduces ATP production inducing AMPK phosphorylation to inhibit the malignant behavior of gastric cancer cells.

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS
ACS Applied Bio Materials Pub Date : 2024-08-01 Epub Date: 2024-06-03 DOI:10.1007/s10863-024-10023-0
Yafang Lai, Xiaofei Wang, Jingrong Ma, Chaoqun Du, Yuyu Wang, Yaxin Wang, Wenzhao Yuan, Mingwei Zhao
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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.

Abstract Image

敲除 EIF2AK2-OAS1 轴可减少 ATP 生成,诱导 AMPK 磷酸化,从而抑制胃癌细胞的恶性行为。
能量代谢一直是癌症进展和靶向治疗的热门话题,而探索癌细胞能量代谢通路中基因的作用已成为解决这一问题的关键。真核翻译起始因子 2α 激酶 2(EIF2AK2)在癌症和能量代谢紊乱中发挥着调控作用。事实上,EIF2AK2 在能量代谢中的作用一直被低估。本研究旨在揭示 EIF2AK2 在胃癌(GC)进展和转移中的表达特异性,并证明 EIF2AK2 在 GC 细胞的能量代谢、细胞骨架、增殖、死亡和转移途径中的作用。从机理上讲,EIF2AK2过表达促进细胞骨架重塑和ATP生成,介导细胞增殖和转移,上调OAS1表达,降低p-AMPK表达,抑制GC细胞凋亡。相反,敲除 EIF2AK2 则会产生相反的效果。然而,过表达 OAS1 会介导线粒体膜电位的上调,促进 ATP 的产生和 NAD+/NADH 的比例,但敲除 OAS1 会抑制上述效应。此外,敲除 OAS1 对 EIF2AK2 的表达没有影响,但抑制了 AMPK 并上调了 p-AMPK 的表达。总之,我们的研究发现 EIF2AK2 和 OAS1 是以前未曾描述过的 GC 细胞能量代谢调节因子。我们推测,EIF2AK2-OAS1轴可能通过影响ATP的产生来诱导AMPK磷酸化,从而调节能量代谢并抑制癌细胞的恶性行为,这表明EIF2AK2是癌细胞进展的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ACS Applied Bio Materials
ACS Applied Bio Materials Chemistry-Chemistry (all)
CiteScore
9.40
自引率
2.10%
发文量
464
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