ACAGT‐007a, an anti‐cancer compound that modulates ERK MAPK signaling, induces nuclear enrichment of phosphorylated ERK in T3M4 pancreatic cancer cells
ACAGT‐007a, an anti‐cancer compound that modulates ERK MAPK signaling, induces nuclear enrichment of phosphorylated ERK in T3M4 pancreatic cancer cells
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ACAGT-007a 是一种调节 ERK MAPK 信号传导的抗癌化合物，可诱导 T3M4 胰腺癌细胞中磷酸化 ERK 的核富集
DOI：
10.1111/gtc.13026
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发表时间：
2023
期刊：
影响因子：
2.1
通讯作者：
Sugiura Reiko
中科院分区：
文献类型：
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作者：
Khandakar Golam Iftakhar;Miyamoto Yoichi;Satoh Ryosuke;Kishimoto Kenta;Xie Mingzuo;Shih Mengyu;Takasaki Teruaki;Tanabe Genzoh;Oka Masahiro;Sugiura Reiko
细胞外信号调节激酶（ERK）信号通路对于细胞增殖至关重要，并且在胰腺癌等人类肿瘤中经常失调。 ACAGT-007a (GT-7) 是一种抗癌化合物，可刺激 ERK 磷酸化，从而诱导 T3M4 胰腺癌细胞的生长抑制和凋亡。然而，GT-7 如何刺激 ERK 磷酸化并诱导 ERK 活性 T3M4 细胞凋亡仍不清楚。为了研究其机制，我们对 T3M4 细胞中 GT-7 介导的 ERK 磷酸化进行了时空分析。免疫印迹显示GT-7在1小时内刺激ERK磷酸化，2小时后更为显着。重要的是，仅在与 GT-7 孵育 2 小时后才观察到通过切割的 Caspase-3 评估的细胞凋亡诱导。免疫荧光染色显示，与 GT-7 孵育 1 小时后，细胞核中磷酸化 ERK（磷酸化 ERK）富集。分级实验表明，GT-7 在 1 小时内增加细胞质中的磷酸化 ERK 水平，而与 GT-7 孵育 2 小时后观察到细胞核磷酸化 ERK 积累。 U0126 抑制 MEK 显着减少核磷酸化 ERK 分布和 GT-7 刺激的细胞凋亡诱导。因此，GT-7可能启动细胞质中ERK磷酸化的诱导，从而导致细胞核中磷酸化ERK的富集。 GT-7 引起的核磷酸化 ERK 积累先于 T3M4 细胞凋亡诱导，并且可能是诱导细胞凋亡的基础。
The extracellular‐signal‐regulated‐kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as pancreatic cancers. ACAGT‐007a (GT‐7), an anti‐cancer compound, stimulates ERK phosphorylation, thereby inducing growth inhibition and apoptosis in T3M4 pancreatic cancer cells. However, how GT‐7 stimulates ERK phosphorylation and induces apoptosis in ERK‐active T3M4 cells remains unclear. To look into the mechanism, we performed a spatiotemporal analysis of ERK phosphorylation mediated by GT‐7 in T3M4 cells. The immunoblotting showed that GT‐7 stimulates ERK phosphorylation within 1 h, which was more remarkable after 2 h. Importantly, apoptosis induction as evaluated by the cleaved Caspase‐3 was observed only after 2‐h incubation with GT‐7. The immunofluorescence staining revealed the enrichment of phosphorylated ERK (phospho‐ERK) in the nucleus upon 1‐h incubation with GT‐7. Fractionation experiments showed that GT‐7 increases phospho‐ERK levels in the cytoplasm within 1 h, whereas nuclear phospho‐ERK accumulation is observed after 2‐h incubation with GT‐7. MEK inhibition by U0126 significantly diminishes nuclear phospho‐ERK distribution and apoptosis induction stimulated by GT‐7. Thus, GT‐7 may initiate the induction of ERK phosphorylation in the cytoplasm, which leads to phospho‐ERK enrichment in the nucleus. This nuclear phospho‐ERK accumulation by GT‐7 precedes and may underlie apoptosis induction in T3M4.