Department of Gynecology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, China.
School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Eur J Pharmacol. 2023 Oct 5;956:175935. doi: 10.1016/j.ejphar.2023.175935. Epub 2023 Aug 2.
The highly conserved RNA-binding protein LIN28B and focal adhesion kinase (FAK) are significantly upregulated in ovarian cancer (OC), serving as markers for disease progression and prognosis. Nonetheless, the correlation between LIN28B and FAK, as well as the pharmacological effects of the LIN28 inhibitor C1632, in OC cells have not been elucidated. The present study demonstrates that C1632 significantly reduced the rate of DNA replication, arrested the cell cycle at the G0/G1 phase, consequently reducing cell viability, and impeding clone formation. Moreover, treatment with C1632 decreased cell-matrix adhesion, as well as inhibited cell migration and invasion. Further mechanistic studies revealed that C1632 inhibited the OC cell proliferation and migration by concurrently inhibiting LIN28 B/let-7/FAK signaling pathway and FAK phosphorylation. Furthermore, C1632 exhibited an obvious inhibitory effect on OC cell xenograft tumors in mice. Altogether, these findings identified that LIN28 B/let-7/FAK is a valuable target in OC and C1632 is a promising onco-therapeutic agent for OC treatment.
高度保守的 RNA 结合蛋白 LIN28B 和粘着斑激酶 (FAK) 在卵巢癌 (OC) 中显著上调，作为疾病进展和预后的标志物。然而，LIN28B 和 FAK 之间的相关性，以及 LIN28 抑制剂 C1632 在 OC 细胞中的药理作用尚未阐明。本研究表明，C1632 可显著降低 DNA 复制率，将细胞周期阻滞在 G0/G1 期，从而降低细胞活力并抑制克隆形成。此外，用 C1632 处理可降低细胞基质黏附，并抑制细胞迁移和侵袭。进一步的机制研究表明，C1632 通过同时抑制 LIN28B/let-7/FAK 信号通路和 FAK 磷酸化来抑制 OC 细胞的增殖和迁移。此外，C1632 对小鼠 OC 细胞异种移植肿瘤表现出明显的抑制作用。总之，这些发现表明 LIN28B/let-7/FAK 是 OC 的一个有价值的靶点，C1632 是治疗 OC 的一种有前途的肿瘤治疗药物。
