Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth.
Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth.
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葡萄膜黑色素瘤（UM）是成人中最常见的眼癌，其扩散到肝脏对患者的预后很差。目前治疗UM只有一种治疗选择，因此，有必要更好地了解UM转移扩散的生物学，以便开发新的治疗方法。我们认为来自肝脏的生长因子促进了UM的转移，在这里，我们研究了胰岛素样生长因子及其受体（IGF-1和IGF-1R）信号在UM生长中的作用。我们发现，通过小分子抑制剂NT157抑制IGF-1R底物，胰岛素受体底物-1/2 (IRS-1/2)，导致多种UM细胞系的细胞存活，迁移和凋亡减少。重要的是，在我们的体内模型中，我们已经表明N157治疗可以减少UM肿瘤的生长，这表明靶向IGF-1/IGF-1R信号可能是一种潜在的治疗策略。葡萄膜黑色素瘤起源于眼睛并转移到肝脏，预后差，只有一种批准的治疗选择。我们假设肝源性生长因子可能有助于UM的生长。因此，我们研究了IGF-1/IGF-1R信号在UM中的作用。在这里，我们发现胰岛素受体底物IRS-1在UM细胞和肿瘤中都过表达。由于我们之前观察到IGF-1R抗体治疗在UM中没有临床效果，我们研究了NT157 （IRS-1/2的小分子抑制剂）在UM中阻断这一途径的潜力。NT157处理多个UM细胞系导致细胞生长和迁移减少，细胞凋亡增加。在体内、鸡蛋毛囊尿囊膜（CAM）和皮下小鼠模型中，该处理也显著抑制了UM肿瘤的生长，验证了体外效果。在机制上，通过逆相蛋白阵列（RPPA），我们发现在NT157处理下，PI3K/AKT通路（IGF-1信号的下游介质）发生了显著的蛋白质组学变化。综上所述，这些结果表明NT157通过抑制UM中的IGF-1信号传导抑制细胞在体外的生长、存活和迁移，以及体内的肿瘤生长。
Uveal melanoma (UM) is the most common eye cancer in adults and its spreading to the liver has poor outcomes for the patients. There is currently only one therapeutic option for treating UM, hence, there is a need for a better understanding of the biology of UM metastatic spreading in order to develop novel therapies. We think that the growth factors originating from the liver contribute to UM metastasis, and here, we have investigated the role of insulin-like growth factor and its receptor (IGF-1 and IGF-1R) signaling in UM growth. We found that inhibiting the IGF-1R substrates, insulin receptor substrates-1/2 (IRS-1/2) through a small molecule inhibitor, NT157, resulted in a reduction of cell survival, migration and increased apoptosis in multiple UM cell lines. Importantly, in our in vivo models, we have shown that N157 treatment reduces UM tumor growth, indicating that targeting IGF-1/IGF-1R signaling could be a potential therapeutic strategy. Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.
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影响因子：
2.2
作者：
Mattei J;Ballhausen A;Bassett R;Shephard M;Chattopadhyay C;Hudgens C;Tetzlaff M;Woodman S;Sato T;Patel SP
通讯作者：
Patel SP
影响因子：
45.3
作者：
Maki, Robert G.
通讯作者：
Maki, Robert G.
影响因子：
11.2
作者：
Reuveni H;Flashner-Abramson E;Steiner L;Makedonski K;Song R;Shir A;Herlyn M;Bar-Eli M;Levitzki A
通讯作者：
Levitzki A
DOI：
10.1186/1478-811x-7-14
发表时间：
2009-06-17
期刊：
Cell communication and signaling : CCS
影响因子：
--
作者：
Mardilovich K;Pankratz SL;Shaw LM
通讯作者：
Shaw LM
影响因子：
158.5
作者：
Nathan, Paul;Hassel, Jessica C.;Piperno-Neumann, Sophie
通讯作者：
Piperno-Neumann, Sophie