Department of Physiology and Pharmacology, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil.
Department of Biochemistry and Molecular Biology, Federal University of Ceará, Fortaleza, Brazil.
J Cell Biochem. 2021 Oct;122(10):1376-1388. doi: 10.1002/jcb.30015. Epub 2021 Jun 23.
Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer.
胃癌是世界上最常见和最致命的癌症之一，治疗失败后预后不良在文献中广泛报道。在这种情况下，激酶已被认为是胃癌靶向治疗的一个相关选择。在这里，我们探讨了 AURKA 抑制剂的抗增殖和抗迁移作用及其作为胃癌生物标志物的预后和治疗价值。总共筛选了 145 种激酶抑制剂，以评估其在胃癌细胞系中的细胞毒性或细胞抑制作用。我们使用 Alamar Blue 测定法、流式细胞术、定量聚合酶链反应以及观察 caspase 3/7 活性和细胞迁移，研究了 AURKA 抑制剂的抗增殖、促凋亡和抗迁移作用。此外，还评估了 AURKA 在胃细胞系和胃肿瘤组织中的过表达。在 145 种抑制剂中，有两种表现出最高的抗增殖作用。这两种分子都可以通过 caspase 3/7 途径诱导细胞凋亡，此外还可以抑制癌细胞迁移，主要是 AURKA 抑制剂。此外，分子对接分析表明，GW779439X 与一种描述良好的抑制剂具有相似的能量，在 AURKA 酶的活性部位相互作用。我们的研究在胃癌细胞系和胃肿瘤组织中发现了 AURKA 的过表达，表明其在癌症患者中的过表达与低生存率相关。因此，除了为患者的诊断和估计生存提供有力信息外，AURKA 作为胃癌的潜在标志物是可行的。AURKA 可被视为一种新的分子靶点，用于胃癌的预后和治疗。
