Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Department of Oncology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.
Biomed Pharmacother. 2022 Apr;148:112665. doi: 10.1016/j.biopha.2022.112665. Epub 2022 Feb 26.
Gastric cancer is a common gastrointestinal malignancy worldwide, with a high mortality rate and poor prognosis. Esomeprazole (ESO) has been shown to have anticancer activity by affecting cell growth and autophagy and its mechanism in gastric cancer cells is evident. The PI3K/AKT/FOXO3a pathway is central in cancers. 3-Methyladenine (3-MA), a dual inhibitor of PI3K and autophagy, plays a synergistic role in combination with antitumor agents. In this study, we assessed the role of ESO on the PI3K/AKT/FOXO3a pathway and the beneficial effects of ESO combined with 3-MA in gastric cancer cells. Cell viability, proliferation, invasion, migration, apoptosis, autophagy, and protein expression were detected by CCK-8, EdU, Transwell, flow cytometry, immunofluorescence assay, and western blot. ESO decreased cell viability in a concentration- and time-dependent manner and increased autophagy with upregulation of LC3II and P62. Additionally, ESO inhibited the proliferation, migration, and invasion and induced the apoptosis of gastric cancer cells in a concentration-dependent manner. ESO inhibited PI3K/AKT/FOXO3a signaling and EGFR and SKP2 expression concentration-dependent. 3-MA enhanced the antiproliferative activity of ESO and synergistically inhibited PI3K/FOXO3a signaling and the expression of EGFR but not SKP2. Furthermore, pretreatment with the EGFR inhibitor AG1478 enhanced the antiproliferative activity of ESO in gastric cancer cells. In conclusion, our results suggested that the PI3K inhibitor 3-MA promotes the antiproliferative activity of ESO in gastric cancer cells by synergistically downregulating EGFR via the PI3K/FOXO3a pathway.
胃癌是一种常见的胃肠道恶性肿瘤，全球死亡率和预后不良。埃索美拉唑（ESO）已被证明具有抗癌活性，可影响细胞生长和自噬，其在胃癌细胞中的机制很明显。PI3K/AKT/FOXO3a 通路在癌症中起着核心作用。3-甲基腺嘌呤（3-MA）是一种 PI3K 和自噬的双重抑制剂，与抗肿瘤药物联合使用具有协同作用。在本研究中，我们评估了 ESO 对 PI3K/AKT/FOXO3a 通路的作用，以及 ESO 与 3-MA 联合应用对胃癌细胞的有益影响。通过 CCK-8、EdU、Transwell、流式细胞术、免疫荧光法和 Western blot 检测细胞活力、增殖、侵袭、迁移、凋亡、自噬和蛋白表达。ESO 呈浓度和时间依赖性降低细胞活力，并增加自噬，上调 LC3II 和 P62。此外，ESO 呈浓度依赖性抑制胃癌细胞的增殖、迁移和侵袭，并诱导其凋亡。ESO 抑制 PI3K/AKT/FOXO3a 信号转导和 EGFR 和 SKP2 的表达呈浓度依赖性。3-MA 增强了 ESO 的抗增殖活性，并协同抑制 PI3K/FOXO3a 信号转导和 EGFR 的表达，但不抑制 SKP2。此外，用 EGFR 抑制剂 AG1478 预处理可增强 ESO 在胃癌细胞中的抗增殖活性。综上所述，我们的研究结果表明，PI3K 抑制剂 3-MA 通过协同下调 PI3K/FOXO3a 通路中的 EGFR，促进 ESO 在胃癌细胞中的抗增殖活性。
