Department of Medical Physiology, College of Medicine, King Khalid University, Abha, Saudi Arabia.
Faculty of Medicine, Department of Medical Physiology, Cairo University, Cairo, Egypt.
Clin Exp Pharmacol Physiol. 2020 Jun;47(6):1092-1102. doi: 10.1111/1440-1681.13288. Epub 2020 Mar 15.
This study investigated if EX-527 has an anti-tumour effect in SKOV-3 and OVCAR-3 ovarian cancer (OC) cell lines and if this effect involves the SIRT1/NF-κB axis. Cells were cultured in the presence or absence of EX-527, a selective SIRT-1 inhibitor. Exendin-4 significantly induced cell death in both cell lines and inhibited cell migration and invasion. Also, it decreased protein levels of Bcl-2, MMP-9, and ICAM-1 and increased those of Bax, cyclin D1 and cleaved caspase-3. Mechanistically, Exendin-4 increased the activity and nuclear accumulation of SIRT1 and decreased nuclear levels of NF-κB p65; acetylated levels of NF-κB p65, and cytoplasmic levels of p-IKKα and p-IκBα. EX-527 partially ameliorated the effect of Exendin-4 on cell death, migration, and invasion, as well as on the expression of Bcl-2, MMP-9, Bax, cleaved caspase-3 and ICAM-1. In addition, EX-527 did not affect the levels of nuclear p65 and p-p65 (Ser536); p-IκBα (Ser32) and p-IKKαβ. In conclusion, Exendin-4 can suppress OC by inhibiting NF-kB through SIRT1 dependent and independent mechanisms.
本研究旨在探讨 EX-527 是否对 SKOV-3 和 OVCAR-3 卵巢癌细胞系具有抗肿瘤作用，以及这种作用是否涉及 SIRT1/NF-κB 轴。细胞在 EX-527（一种选择性 SIRT-1 抑制剂）存在或不存在的情况下进行培养。Exendin-4 显著诱导两种细胞系的细胞死亡，并抑制细胞迁移和侵袭。此外，它降低了 Bcl-2、MMP-9 和 ICAM-1 的蛋白水平，增加了 Bax、细胞周期蛋白 D1 和 cleaved caspase-3 的蛋白水平。在机制上，Exendin-4 增加了 SIRT1 的活性和核积累，降低了 NF-κB p65 的核水平；NF-κB p65 的乙酰化水平和细胞质中 p-IKKα 和 p-IκBα 的水平。EX-527 部分改善了 Exendin-4 对细胞死亡、迁移和侵袭以及 Bcl-2、MMP-9、Bax、cleaved caspase-3 和 ICAM-1 表达的影响。此外，EX-527 不影响核 p65 和 p-p65（Ser536）；p-IκBα（Ser32）和 p-IKKαβ 的水平。总之，Exendin-4 可以通过 SIRT1 依赖和独立的机制抑制 NF-κB 来抑制 OC。
