Aptamer-SH2 superbinder-based targeted therapy for pancreatic ductal adenocarcinoma.
Aptamer-SH2 superbinder-based targeted therapy for pancreatic ductal adenocarcinoma.
复制标题
适体SH2超结合物靶向治疗胰腺导管腺癌
DOI：
10.1002/ctm2.337
复制
发表时间：
2021-03
影响因子：
10.6
通讯作者：
Cao X
中科院分区：
文献类型：
--
作者：
Liu AD;Zhou J;Bi XY;Hou GQ;Li SS;Chen Q;Xu H;Cao X
胰腺导管腺癌（PDAC）是所有实体瘤中预后最差的，诊断后5年生存率低于10%，中位生存期为6个月。许多靶向药物已被开发和评估，以提高PDAC患者的生存获益。不幸的是，大多数药物已被证明是无效的，主要是由于致密的基质和复杂的信号通路的PDAC。在这里，我们证明了Aptamer-SH 2超结合剂-（Arg）9缀合物对治疗PDAC的有效性。在这种偶联物中，针对PDAC细胞系选择的DNA适体赋予特异性识别和结合基质中的PDAC细胞和活化的胰腺星状细胞（PSC）的功能;细胞穿透肽（Arg）9促进融合蛋白的细胞内递送; SH 2超结合剂对肿瘤细胞中多种基于磷酸酪氨酸（pY）的信号通路进行剧烈阻断。通过生物信息学筛选重新分析PDAC相关pY。将XQ-2d和SH 2超结合剂-（Arg）9与BMH交联以形成XQ-2d-SH 2 CM-（Arg）9缀合物。利用免疫荧光来评估缀合物进入细胞的效力。进行MTT和伤口愈合测定以分别评价PANC-1和BxPC-3细胞的增殖或迁移。Western印迹和Pulldown测定显示缀合物影响几种基于pY的信号传导途径。使用荷瘤小鼠验证XQ-2d-SH 2 CM-（Arg）9抑制癌细胞生长和转移。XQ-2d-His-SH 2 CM-（Arg）9偶联物通过阻断几种pY相关信号级联的活性而有效抑制PDAC细胞的增殖、侵袭和转移。XQ-2d-His-SH 2 CM-（Arg）9可清除PDAC致密间质到达肿瘤组织。XQ-2d-SH 2 CM-（Arg）9偶联物能有效破坏胰腺间质，在体内外均能通过调节肿瘤细胞的增殖和转移而发挥抗肿瘤作用，毒副作用小，有望成为PDAC的靶向治疗药物。 PDAC细胞和PSC中XQ-2d-His-SH 2 CM-（Arg）9的示意图。XQ-2d-His-SH 2 CM-（Arg）9可结合并渗透入PSCs、PDSCs，减少ECM分泌。XQ-2d-His-SH 2 CM-（Arg）9可到达肿瘤组织，识别并进入PDAC细胞。XQ-2d-His-SH 2 CM-（Arg）9可通过捕获含pY的蛋白质并阻断PDAC细胞中多种基于pY的信号通路而作为广谱抑制剂发挥作用。
Pancreatic ductal adenocarcinoma (PDAC) exhibits the poorest prognosis of all solid tumors with a 5‐year survival rate of less than 10% and a median survival of 6 months after diagnosis. Numerous targeted agents have been developed and evaluated to improve the survival benefit in patients with PDAC. Unfortunately, most agents have been proven futile mainly owing to the dense stroma and the sophisticated signaling pathways of PDAC. Here, we show the potent effectiveness of Aptamer‐SH2 superbinder‐(Arg)9 conjugate on the treatment of PDAC. In this conjugate, DNA aptamer selected against PDAC cell line confers the function of specifically recognizing and binding to the PDAC cells and activated pancreatic stellate cells (PSCs) in stroma; cell penetrating peptide (Arg)9 facilitates the intracellular delivery of fused proteins; SH2 superbinder conducts the drastic blockade of multiple phosphotyrosines (pY)‐based signaling pathways in tumor cells. PDAC‐associated pY were reanalyzed by bioinformatics screen. XQ‐2d and SH2 superbinder‐(Arg)9 were crosslinked with BMH to form XQ‐2d‐SH2 CM‐(Arg)9 conjugate. Immunofluorescence was utilized to assess the potency of the conjugate entering cells. MTT and wound healing assays were performed to evaluate the proliferation or migration of PANC‐1 and BxPC‐3 cells, respectively. Western blot and Pulldown assays revealed that conjugate influenced several pY‐based signaling pathways. Tumor‐bearing mice were used to validate XQ‐2d‐SH2 CM‐(Arg)9, which restrained the growth and metastasis of cancer cells. XQ‐2d‐His‐SH2 CM‐(Arg)9 conjugate restrained proliferation, invasion, and metastasis of PDAC cells with potent efficacy via blocking the activity of several pY‐related signaling cascades. XQ‐2d‐His‐SH2 CM‐(Arg)9 could eliminate the dense stroma of PDAC and then arrive at tumor tissues. XQ‐2d‐SH2 CM‐(Arg)9 conjugate may efficiently destroy the pancreatic stroma and show potent antitumor efficacy with minimal toxic effect by regulating tumor cell proliferation and metastasis in vitro and in vivo, which makes it to be a promising targeted therapy of PDAC. Schematic diagram of XQ‐2d‐His‐SH2 CM‐(Arg)9 in PDAC cells and PSCs. XQ‐2d‐His‐SH2 CM‐(Arg)9 could bind and penetrate into PSCs, inactivate PSCs, and decrease ECM secretion. XQ‐2d‐His‐SH2 CM‐(Arg)9 could reach tumor tissues, recognize, and enter into the PDAC cells. XQ‐2d‐His‐SH2 CM‐(Arg)9 could function as a broad‐spectrum inhibitor via capturing pY‐containing proteins and blocking multitude pY‐based signaling pathways in PDAC cells.
登录
查看更多内容
DOI：
10.1158/1078-0432.ccr-14-0610
发表时间：
2015-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Kadera BE;Toste PA;Wu N;Li L;Nguyen AH;Dawson DW;Donahue TR
通讯作者：
Donahue TR
灵敏、稳健且经济高效的酪氨酸磷酸化蛋白质组分析方法
影响因子：
7.4
作者：
Dong, Mingming;Bian, Yangyang;Ye, Mingliang
通讯作者：
Ye, Mingliang
影响因子：
29.4
作者：
Bachem, MG;Schneider, E;Adler, G
通讯作者：
Adler, G
YY1 靶向微管蛋白聚合促进蛋白，通过 p38/MAPK 和 PI3K/AKT 途径抑制胰腺癌的迁移、侵袭和血管生成
影响因子：
8.8
作者：
Chen, Qun;Yang, Chuang;Jiang, Kui-Rong
通讯作者：
Jiang, Kui-Rong
影响因子：
17.1
作者：
Barth BM;Sharma R;Altinoğlu EI;Morgan TT;Shanmugavelandy SS;Kaiser JM;McGovern C;Matters GL;Smith JP;Kester M;Adair JH
通讯作者：
Adair JH