Hemocenter of Ribeirão Preto, 14051-140 Ribeirão Preto, SP, Brazil.
Department of Biochemistry and Immunology, Ribeirão Preto Medical School - University of São Paulo, Ribeirão Preto, SP, Brazil.
Leuk Lymphoma. 2019 Nov;60(11):2658-2668. doi: 10.1080/10428194.2019.1607326. Epub 2019 May 7.
Lipid rafts are ordered membrane domains, which provide an environment for the proteins participating in signal transduction. Perifosine is an alkylphospholipid (APL) that inhibits the AKT pathway, cytotoxic to neoplastic cells. We have shown that the lipid raft adaptor protein NTAL is a target of APLs in leukemic cells. Using human mantle cell lymphoma (MCL) Granta-519 cell line we showed here that perifosine decreased NTAL in lipid raft fractions reducing AKT phosphorylation before apoptosis. We also showed that the NTAL-knockdown by shRNA induced a state of reduced AKT activation. Experimental NTAL-knockdown in NSG mouse MCL xenografts reduced AKT activity, increased the basal apoptotic rate by 3-fold ( = 8) and decreased tumor weight by 2.7-fold ( = 5), indicating that NTAL participates in tumor growth. NTAL protein was detected by western blotting in circulating cells of 7 of 8 MCL patients in the leukemic phase, suggesting involvement in the progression of the disease.
脂筏是一种有序的膜结构域，为参与信号转导的蛋白质提供了一个环境。Perifosine 是一种烷基磷脂（APL），可抑制 AKT 通路，对肿瘤细胞具有细胞毒性。我们已经表明，脂质筏衔接蛋白 NTAL 是白血病细胞中 APL 的靶标。在这里，我们使用人套细胞淋巴瘤（MCL）Granta-519 细胞系表明，Perifosine 减少了脂筏部分的 NTAL，从而在凋亡前减少了 AKT 的磷酸化。我们还表明，shRNA 诱导的 NTAL 敲低会导致 AKT 激活减少。在 NSG 小鼠 MCL 异种移植模型中进行的实验性 NTAL 敲低可降低 AKT 活性，使基础凋亡率增加 3 倍（=8），肿瘤重量减少 2.7 倍（=5），表明 NTAL 参与了肿瘤生长。在白血病期的 8 例 MCL 患者中有 7 例的循环细胞中通过 Western blot 检测到了 NTAL 蛋白，这表明它参与了疾病的进展。
