A murine monoclonal antibody directed against the carboxyl-terminal domain of GRP78 suppresses melanoma growth in mice
A murine monoclonal antibody directed against the carboxyl-terminal domain of GRP78 suppresses melanoma growth in mice
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DOI：
10.1097/cmr.0b013e32835312fd
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发表时间：
2012-06-01
影响因子：
2.2
通讯作者：
Pizzo, Salvatore V.
中科院分区：
文献类型：
--
作者：
de Ridder, Gustaaf G.;Ray, Rupa;Pizzo, Salvatore V.
HSP70家族成员GRP78是一种选择性肿瘤标志物，在许多肿瘤细胞类型（包括黑色素瘤）表面上调，在那里它作为一种生长因子受体样蛋白。受体识别的蛋白酶抑制剂α(2)-巨球蛋白（α M-2*）是GRP78最具特征的配体，但在黑色素瘤和其他癌症患者中，针对GRP78 nh2末端结构域的自身抗体会与肿瘤细胞表面GRP78发生反应。这引起促增殖和抗凋亡的信号级联的激活。然而，针对GRP78的cooh末端结构域的抗体上调p53介导的促凋亡信号，导致细胞死亡。在这里，我们描述了三种新型小鼠单克隆抗体的结合特性、细胞信号特性和下游细胞效应。nh2末端结构域反应性抗体N88在体外模拟α M-2*作为配体，驱动pi3激酶依赖性的Akt活化和随后的细胞增殖刺激。cooh末端结构域反应性抗体C38作为α M-2*和N88的拮抗剂，而另一种C107则直接诱导体外细胞凋亡。在小鼠B16F1黑色素瘤侧腹肿瘤模型中，我们发现N88能加速肿瘤生长，而C107在肿瘤植入前（P < 0.005）和植入后（P < 0.05）均能显著减缓肿瘤生长。黑色素瘤杂志22:225-235 (C) 2012 Wolters Kluwer Health垂直bar Lippincott Williams & Wilkins。
The HSP70 family member GRP78 is a selective tumor marker upregulated on the surface of many tumor cell types, including melanoma, where it acts as a growth factor receptor-like protein. Receptor-recognized forms of the proteinase inhibitor alpha(2)-macroglobulin (alpha M-2*) are the best-characterized ligands for GRP78, but in melanoma and other cancer patients, autoantibodies arise against the NH2-terminal domain of GRP78 that react with tumor cell-surface GRP78. This causes the activation of signaling cascades that are proproliferative and antiapoptotic. Antibodies directed against the COOH-terminal domain of GRP78, however, upregulate p53-mediated proapoptotic signaling, leading to cell death. Here, we describe the binding characteristics, cell signaling properties, and downstream cellular effects of three novel murine monoclonal antibodies. The NH2-terminal domain-reactive antibody, N88, mimics alpha M-2* as a ligand and drives PI 3-kinase-dependent activation of Akt and the subsequent stimulation of cellular proliferation in vitro. The COOH-terminal domain-reactive antibody, C38, acts as an antagonist of both alpha M-2* and N88, whereas another, C107, directly induces apoptosis in vitro. In a murine B16F1 melanoma flank tumor model, we demonstrate the acceleration of tumor growth by treatment with N88, whereas C107 significantly slowed tumor growth whether administered before (P < 0.005) or after (P < 0.05) tumor implantation. Melanoma Res 22: 225-235 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.