磷脂酶 D1 (PLD1) 通过影响细胞增殖、存活、侵袭、转移、血管生成、耐药性和肿瘤微环境的调节，促进癌症的发生和进展。它在这些过程中的核心作用使其成为新型癌症治疗的有希望的目标，旨在抑制其活性并破坏其调节的信号通路。在本研究中，我们旨在使用新型肽抑制剂 TAT-TVTSP 来研究 PLD1 抑制对胃癌细胞生长的影响。 PLD1在癌症进展中发挥作用，通过水解催化磷脂酰胆碱转化为胆碱和磷脂酸。为了有效地靶向细胞中的 PLD1，我们通过将 PLD1 抑制肽 (TVTSP) 与细胞穿透肽 (TAT) 融合来设计 TAT-TVTSP。我们观察到 TAT-TVTSP 有效抑制 AGS 胃癌细胞中的 PLD1 活性。此外，TAT-TVTSP 显着抑制雷帕霉素信号通路的哺乳动物靶标，包括关键下游靶标的磷酸化，如 S6K1、AKT、S473、糖原合酶激酶 3b 和叉头框 O1。 TAT-TVTSP 不会诱导细胞死亡，但它通过 AKT 磷酸化激活 p21 和 p27 来触发细胞周期停滞。功能测定表明，TAT-TVTSP 显着损害 AGS 细胞的集落形成能力，从而抑制细胞增殖。 Transwell 和伤口愈合试验表明，这种肽破坏了对癌症进展至关重要的细胞行为，例如迁移和侵袭。在体内，TAT-TVTSP 显着减少胃癌异种移植模型中的肿瘤生长，且没有任何毒性。总体而言，我们的结果表明 TAT-TVTSP 是一种针对 PLD1 介导的癌症的新型治疗剂。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Phospholipase D1 (PLD1) contributes to cancer development and progression through its effects on cell proliferation, survival, invasion, metastasis, angiogenesis, drug resistance, and modulation of the tumor microenvironment. Its central role in these processes makes it a promising target for novel cancer treatments aimed at inhibiting its activity and disrupting the signaling pathways it regulates. In this study, we aimed to investigate the effect of PLD1 inhibition on gastric cancer cell growth using a novel peptide inhibitor, TAT-TVTSP. PLD1, which plays a role in cancer progression, catalyzes the conversion of phosphatidylcholine into choline and phosphatidic acid through hydrolysis. To effectively target PLD1 in cells, we engineered TAT-TVTSP by fusing a PLD1-inhibitory peptide (TVTSP) with a cell-penetrating peptide (TAT). We observed that TAT-TVTSP effectively inhibited PLD1 activity in AGS gastric cancer cells. Moreover, TAT-TVTSP significantly inhibited the mammalian target of the rapamycin signaling pathway, including the phosphorylation of key downstream targets such as S6K1, AKT, S473, glycogen synthase kinase-3b, and forkhead box O1. TAT-TVTSP did not induce cell death, but it triggered cell cycle arrest by activating p21 and p27 via AKT phosphorylation. Functional assays revealed that TAT-TVTSP significantly impaired the colony-forming ability of AGS cells, thus inhibiting cell proliferation. Transwell and wound-healing assays revealed that this peptide disrupted the cellular behaviors critical to cancer progression, such as migration and invasion. In vivo, TAT-TVTSP significantly reduced tumor growth in the xenograft model of gastric cancer without any toxicity. Overall, our results suggest that TAT-TVTSP is a novel therapeutic agent for PLD1-mediated cancers.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.