Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
Cancer Institute, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Int J Mol Sci. 2023 Sep 26;24(19):14566. doi: 10.3390/ijms241914566.
Triple-negative breast cancer (TNBC) is the most fatal subtype of breast cancer; however, effective treatment strategies for TNBC are lacking. Therefore, it is important to explore the mechanism of TNBC metastasis and identify its therapeutic targets. Dysregulation of ETHE1 leads to ethylmalonic encephalopathy in humans; however, the role of ETHE1 in TNBC remains elusive. Stable cell lines with ETHE1 overexpression or knockdown were constructed to explore the biological functions of ETHE1 during TNBC progression in vitro and in vivo. Mass spectrometry was used to analyze the molecular mechanism through which ETHE1 functions in TNBC progression. ETHE1 had no impact on TNBC cell proliferation and xenograft tumor growth but promoted TNBC cell migration and invasion in vitro and lung metastasis in vivo. The effect of ETHE1 on TNBC cell migratory potential was independent of its enzymatic activity. Mechanistic investigations revealed that ETHE1 interacted with eIF2α and enhanced its phosphorylation by promoting the interaction between eIF2α and GCN2. Phosphorylated eIF2α in turn upregulated the expression of ATF4, a transcriptional activator of genes involved in cell migration and tumor metastasis. Notably, inhibition of eIF2α phosphorylation through ISRIB or ATF4 knockdown partially abolished the tumor-promoting effect of ETHE1 overexpression. ETHE1 has a functional and mechanistic role in TNBC metastasis and offers a new therapeutic strategy for targeting ETHE1-propelled TNBC using ISRIB.
三阴性乳腺癌（TNBC）是乳腺癌中最致命的亚型；然而，缺乏针对 TNBC 的有效治疗策略。因此，探索 TNBC 转移的机制并确定其治疗靶点非常重要。ETHE1 的失调会导致人类乙基丙二酸脑病；然而，ETHE1 在 TNBC 中的作用仍不清楚。构建了 ETHE1 过表达或敲低的稳定细胞系，以体外和体内探索 ETHE1 在 TNBC 进展过程中的生物学功能。通过质谱分析来分析 ETHE1 在 TNBC 进展中发挥作用的分子机制。ETHE1 对 TNBC 细胞增殖和异种移植肿瘤生长没有影响，但在体外促进了 TNBC 细胞的迁移和侵袭，以及体内的肺转移。ETHE1 对 TNBC 细胞迁移潜能的影响与其酶活性无关。机制研究表明，ETHE1 与 eIF2α 相互作用，并通过促进 eIF2α 与 GCN2 的相互作用来增强其磷酸化。磷酸化的 eIF2α 转而上调 ATF4 的表达，ATF4 是参与细胞迁移和肿瘤转移的基因的转录激活剂。值得注意的是，通过 ISRIB 抑制 eIF2α 磷酸化或 ATF4 敲低部分消除了 ETHE1 过表达的促肿瘤作用。ETHE1 在 TNBC 转移中具有功能和机制作用，并为使用 ISRIB 靶向 ETHE1 驱动的 TNBC 提供了一种新的治疗策略。
