Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, Shandong Province, China.
Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, Shandong Province, China; Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Wenhua Road, Jinan 250012, Shandong Province, China; Shandong Cancer Hospital and Institute, 440 Jiyan Road, Jinan 250117, Shandong Province, China.
J Pharmacol Sci. 2022 Oct;150(2):56-66. doi: 10.1016/j.jphs.2022.07.001. Epub 2022 Jul 31.
Studies have shown that inhibition of PI3K/AKT signaling is a key strategy for the treatment of tyrosine kinase inhibitor resistance in non-small cell lung cancer (NSCLC). Vasculogenic mimicry (VM) not only accelerates tumor progression but also increases drug-induced resistance. As a tumor suppressor, protein phosphatase 2A (PP2A) is a ubiquitous conserved serine/threonine phosphatase. While its effects and mechanisms on VM formation and invasion in NSCLC remain unclear. The present study aimed to investigate the role of PP2A in VM formation and elucidate the underlying mechanisms. Results showed that PP2A could significantly inhibit VM formation and VM-dependent behavior, including invasion and migration both in vitro and in vivo. Activation of PP2A with FTY720 or Ad-PP2A reduced phosphorylated AKT and inhibited ZEB1 transcription, thereby further downregulating the expression of MMP-2, VE-cadherin, and VEGFR-2, whereas inhibition of PP2A with okadaic acid (OA) or Ad-dn-PP2A exerted the opposite effect. Furthermore, PP2A inhibited tumor growth and VM formation in the xenograft tumor model. PI3K inhibitor BENC-511 could potentiate activation of PP2A, leading to inhibition of p-AKT/ZEB1 and VM formation in vitro and in vivo. This study indicated that PP2A could regulate VM formation in NSCLC through the PI3K/AKT/ZEB1 axis. PP2A reactivation or combination with PI3K inhibitor might be a more effective treatment against advanced NSCLC by inhibiting VM formation.
研究表明，抑制 PI3K/AKT 信号通路是治疗非小细胞肺癌（NSCLC）酪氨酸激酶抑制剂耐药的关键策略。血管生成拟态（VM）不仅加速肿瘤进展，还增加药物诱导的耐药性。蛋白磷酸酶 2A（PP2A）作为一种肿瘤抑制因子，是一种普遍存在的保守丝氨酸/苏氨酸磷酸酶。虽然其对 NSCLC 中 VM 形成和侵袭的作用及其机制尚不清楚。本研究旨在探讨 PP2A 在 VM 形成中的作用，并阐明其潜在机制。结果表明，PP2A 可显著抑制 VM 形成以及 VM 依赖性行为，包括体外和体内的侵袭和迁移。用 FTY720 或 Ad-PP2A 激活 PP2A 可降低磷酸化 AKT 的水平，并抑制 ZEB1 转录，从而进一步下调 MMP-2、VE-cadherin 和 VEGFR-2 的表达，而用 okadaic acid（OA）或 Ad-dn-PP2A 抑制 PP2A 则产生相反的效果。此外，PP2A 抑制了异种移植肿瘤模型中的肿瘤生长和 VM 形成。PI3K 抑制剂 BENC-511 可增强 PP2A 的激活，导致体外和体内 p-AKT/ZEB1 的抑制和 VM 形成。本研究表明，PP2A 可通过 PI3K/AKT/ZEB1 轴调节 NSCLC 中的 VM 形成。PP2A 的再激活或与 PI3K 抑制剂联合使用可能通过抑制 VM 形成成为治疗晚期 NSCLC 的更有效方法。
