Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth.
Usp9x Promotes Survival in Human Pancreatic Cancer and Its Inhibition Suppresses Pancreatic Ductal Adenocarcinoma In Vivo Tumor Growth.
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DOI：
10.1016/j.neo.2017.11.007
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Donato NJ
中科院分区：
文献类型：
--
作者：
Pal A;Dziubinski M;Di Magliano MP;Simeone DM;Owens S;Thomas D;Peterson L;Potu H;Talpaz M;Donato NJ
Usp9x 已成为一些血液系统恶性肿瘤和包括脑、乳腺癌和前列腺等多种实体瘤的潜在治疗靶点。为了检查 Usp9x 致瘤性以及 Usp9x 抑制在人胰腺肿瘤模型中的后果，我们使用已建立的人胰腺肿瘤细胞系（PANC1 和 MIAPACA2）和四种自发永生化人胰腺患者来源肿瘤（PDX）细胞系进行了功能获得和丧失研究。小分子去泛素酶抑制剂 G9 抑制 Usp9x 活性的效果在 2D 和 3D 培养中进行了评估，并在人类肿瘤异种移植物中测试了其功效。 Usp9x 的过度表达增加了 PANC1 细胞的 3D 生长和侵袭，并上调了已知 Usp9x 底物 Mcl-1 和 ITCH 的表达。通过 shRNA 敲低或 G9 处理抑制 Usp9x 可减少 PANC1 和 PDX 细胞系中的 3D 集落形成，诱导 MIAPACA2 细胞快速凋亡，并与 Mcl-1 和 ITCH 蛋白水平降低相关。尽管 G9 治疗减少了体内人 MIAPACA2 肿瘤负荷，但在由组成型 (8041) 和多西环素诱导型 (4668) KrasG12D/Tp53R172H 小鼠胰腺肿瘤建立的小鼠胰腺癌细胞系中，Usp9x 抑制增加并维持了 3D 集落生长，并且对 8041 异种移植物中的肿瘤生长没有显着影响。因此，Usp9x 抑制可能对人 PDAC 具有治疗活性，但基因工程小鼠胰腺肿瘤模型的研究并未预测到这种活性。
Usp9x has emerged as a potential therapeutic target in some hematologic malignancies and a broad range of solid tumors including brain, breast, and prostate. To examine Usp9x tumorigenicity and consequence of Usp9x inhibition in human pancreatic tumor models, we carried out gain- and loss-of-function studies using established human pancreatic tumor cell lines (PANC1 and MIAPACA2) and four spontaneously immortalized human pancreatic patient-derived tumor (PDX) cell lines. The effect of Usp9x activity inhibition by small molecule deubiquitinase inhibitor G9 was assessed in 2D and 3D culture, and its efficacy was tested in human tumor xenografts. Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH. Usp9x inhibition by shRNA-knockdown or by G9 treatment reduced 3D colony formation in PANC1 and PDX cell lines, induced rapid apoptosis in MIAPACA2 cells, and associated with reduced Mcl-1 and ITCH protein levels. Although G9 treatment reduced human MIAPACA2 tumor burden in vivo, in mouse pancreatic cancer cell lines established from constitutive (8041) and doxycycline-inducible (4668) KrasG12D/Tp53R172H mouse pancreatic tumors, Usp9x inhibition increased and sustained the 3D colony growth and showed no significant effect on tumor growth in 8041-xenografts. Thus, Usp9x inhibition may be therapeutically active in human PDAC, but this activity was not predicted from studies of genetically engineered mouse pancreatic tumor models.
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影响因子：
16.6
作者：
Potu H;Peterson LF;Kandarpa M;Pal A;Sun H;Durham A;Harms PW;Hollenhorst PC;Eskiocak U;Talpaz M;Donato NJ
通讯作者：
Donato NJ
影响因子：
4.8
作者：
Trivigno, Donatella;Essmann, Frank;Rudner, Justine
通讯作者：
Rudner, Justine
DOI：
10.1073/pnas.1322198111
发表时间：
2014-03-18
影响因子：
11.1
作者：
Wang, Shan;Kollipara, Rahul K.;Kittler, Ralf
通讯作者：
Kittler, Ralf
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
1.2
作者：
Pal, Anupama;Kleer, Celina G.
通讯作者：
Kleer, Celina G.