通过模拟人 SLURP-1 环 I 的合成肽选择性靶向 α7 烟碱乙酰胆碱受体，为体内表皮样癌提供有效且持久的治疗。
Selective targeting of α7 nicotinic acetylcholine receptor by synthetic peptide mimicking loop I of human SLURP-1 provides efficient and prolonged therapy of epidermoid carcinoma in vivo.
发表日期：2023
作者：
O V Shlepova, M A Shulepko, V O Shipunova, M L Bychkov, I D Kukushkin, I A Chulina, V N Azev, E I Shramova, V A Kazakov, A M Ismailova, Y A Palikova, V A Palikov, E A Kalabina, E A Shaykhutdinova, G A Slashcheva, E A Tukhovskaya, I A Dyachenko, A N Murashev, S M Deyev, M P Kirpichnikov, Z O Shenkarev, E N Lyukmanova
来源：
Frontiers in Cell and Developmental Biology
摘要：
α7型烟碱乙酰胆碱受体（α7-nAChR）促进实体瘤的生长和转移。分泌型 Ly6/uPAR 相关蛋白 1 (SLURP-1) 是上皮细胞产生的 α7-nAChR 的特异性负调节剂。在这里，我们研究了重组 SLURP-1 在表皮样癌 A431 细胞中的抗增殖活性机制以及 SLURP-1 和合成的 21 个氨基酸的活性。在表皮样癌异种移植小鼠模型中模拟其环 I (Oncotag) 的肽。 SLURP-1抑制A431细胞中的有丝分裂途径和转录因子，其抗增殖活性依赖于α7-nAChR。对小鼠进行 10 天的 SLURP-1 或 Oncotag 静脉注射治疗可抑制肿瘤生长和转移，并诱导肿瘤中基因和 microRNA 表达的持续变化。 SLURP-1 和 Oncotag 均未表现出急性毒性。令人惊讶的是，Oncotag 导致更长时间地抑制促癌信号传导，下调促癌 miR-221 的表达，并上调负责控制细胞分化的 KLF4 蛋白的表达。亲和纯化揭示了 SLURP-1 与 α7-nAChR 和 EGFR 的相互作用以及选择性 Oncotag 与 α7-nAChR 的相互作用。因此，基于 Oncotag 的药物选择性抑制 α7-nAChR 可能是一种有前途的癌症治疗策略。版权所有 © 2023 Shlepova, Shulepko, Shipunova, Bychkov, Kukushkin, Chulina, Azev, Shramova, Kazakov, Ismailova, Palikova, Palikov,卡拉宾娜、谢胡特季诺娃、斯拉切娃、图霍夫斯卡娅、迪亚琴科、穆拉舍夫、杰耶夫、基尔皮奇尼科夫、申卡列夫和柳克马诺娃。
α7-Type nicotinic acetylcholine receptor (α7-nAChR) promotes the growth and metastasis of solid tumors. Secreted Ly6/uPAR-Related Protein 1 (SLURP-1) is a specific negative modulator of α7-nAChR produced by epithelial cells. Here, we investigated mechanisms of antiproliferative activity of recombinant SLURP-1 in epidermoid carcinoma A431 cells and activity of SLURP-1 and synthetic 21 a.a. peptide mimicking its loop I (Oncotag) in a xenograft mice model of epidermoid carcinoma. SLURP-1 inhibited the mitogenic pathways and transcription factors in A431 cells, and its antiproliferative activity depended on α7-nAChR. Intravenous treatment of mice with SLURP-1 or Oncotag for 10 days suppressed the tumor growth and metastasis and induced sustained changes in gene and microRNA expression in the tumors. Both SLURP-1 and Oncotag demonstrated no acute toxicity. Surprisingly, Oncotag led to a longer suppression of pro-oncogenic signaling and downregulated expression of pro-oncogenic miR-221 and upregulated expression of KLF4 protein responsible for control of cell differentiation. Affinity purification revealed SLURP-1 interactions with both α7-nAChR and EGFR and selective Oncotag interaction with α7-nAChR. Thus, the selective inhibition of α7-nAChRs by drugs based on Oncotag may be a promising strategy for cancer therapy.Copyright © 2023 Shlepova, Shulepko, Shipunova, Bychkov, Kukushkin, Chulina, Azev, Shramova, Kazakov, Ismailova, Palikova, Palikov, Kalabina, Shaykhutdinova, Slashcheva, Tukhovskaya, Dyachenko, Murashev, Deyev, Kirpichnikov, Shenkarev and Lyukmanova.