Activin A, a member of the transforming growth factor‑β (TGF‑β) superfamily, has been implicated in the tumorigenesis and progression of various cancers. However, it remains unclear whether activin A induces apoptosis in human lung adenocarcinoma cells through the endoplasmic reticulum (ER) stress pathway. In the present study, BrdU, flow cytometry and western blotting were used to examine cell proliferation, apoptosis and protein expression, respectively. The present study revealed that activin A inhibited human lung adenocarcinoma A549 cell proliferation, induced apoptosis, and upregulated the protein levels of C/EBP homologous protein (CHOP), growth arrest and DNA damage‑inducible protein 34 (GADD34), cleaved‑caspase‑3 and caspase‑12. Furthermore, the administration of activin A did not alter the levels of suppressor of mothers against decapentaplegic 3 (Smad3) or phosphorylated (p)‑Smad3 proteins, whereas, it significantly elevated the levels of ActRIIA and p‑extracellular signal regulated kinase proteins 1 and 2 (ERK1/2) proteins in A549 cells. The apoptotic effects of activin A on A549 cells were attenuated by the ERK inhibitor FR180204, which also downregulated CHOP and caspase‑12 protein levels. Additionally, activin A increased intracellular calcium flux in A549 cells, and the calcium ion chelator BAPTA acetoxymethyl ester (BAPTA‑AM) inhibited activin A‑induced A549 cell apoptosis, whereas the calcium agonist ionomycin significantly increased apoptosis of A549 cells induced by activin A. These findings indicated that the activation of the ER stress pathway resulting in apoptosis of A549 cells triggered by activin A is facilitated by the ActRIIA‑ERK1/2 signaling and calcium signaling. The present findings suggest that the agonists of ERK and calcium signaling exhibit promising clinical therapeutic potential for the induction of apoptosis in lung adenocarcinoma.

中文翻译：

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Activin A 通过内质网应激途径诱导人肺腺癌 A549 细胞凋亡。

激活素 A 是转化生长因子 β (TGF-β) 超家族的成员，与多种癌症的发生和进展有关。然而，目前尚不清楚激活素A是否通过内质网（ER）应激途径诱导人肺腺癌细胞凋亡。在本研究中，BrdU、流式细胞术和蛋白质印迹分别用于检测细胞增殖、凋亡和蛋白表达。本研究表明，激活素 A 抑制人肺腺癌 A549 细胞增殖，诱导细胞凋亡，并上调 C/EBP 同源蛋白 (CHOP)、生长停滞和 DNA 损伤诱导蛋白 34 (GADD34)、cleaved-caspase- 的蛋白水平。 3 和 caspase-12。此外，给予激活素 A 并没有改变母亲对十五麻痹 3 (Smad3) 或磷酸化 (p)-Smad3 蛋白的抑制水平，但它显着升高了 ActRIIA 和 p-细胞外信号调节激酶蛋白 1 和A549 细胞中的 2 (ERK1/2) 蛋白。ERK 抑制剂 FR180204 减弱了激活素 A 对 A549 细胞的凋亡作用，该抑制剂还下调了 CHOP 和 caspase-12 蛋白水平。此外，激活素 A 增加了 A549 细胞中的细胞内钙通量，钙离子螯合剂 BAPTA 乙酰氧基甲酯 (BAPTA-AM) 抑制了激活素 A 诱导的 A549 细胞凋亡，而钙激动剂离子霉素显着增加了激活素 A 诱导的 A549 细胞凋亡。这些发现表明，ActRIIA-ERK1/2 信号传导和钙信号传导促进了 ER 应激途径的激活，导致激活素 A 触发的 A549 细胞凋亡。目前的研究结果表明，ERK 和钙信号传导激动剂在诱导肺腺癌细胞凋亡方面表现出有希望的临床治疗潜力。