Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78
Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78
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DOI：
10.1007/s10495-009-0430-y
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发表时间：
2010-02-01
期刊：
影响因子：
7.2
通讯作者：
Pizzo, S. V.
中科院分区：
文献类型：
--
作者：
Misra, U. K.;Pizzo, S. V.
受体识别形式的α 2-巨球蛋白（α M-2*）与癌细胞表面GRP 78结合，GRP 78作为促进增殖和存活的信号受体发挥作用。患有前列腺癌、卵巢癌和皮肤癌的患者可能产生针对α M-2* 结合位点的自身抗体，其是受体激动剂，其存在表明预后不良。相反，针对GPR 78的COOH末端结构域的抗体（抗CTD抗体）是下调促增殖信号传导和上调p53的拮抗剂。未折叠蛋白反应（Unfolded protein response，UPR）信号在细胞存活、增殖和凋亡中起着重要作用。因此，我们研究了抗CTD抗体对1-LN和DU-145前列腺癌细胞中UPR信号传导的影响。用这种抗体处理这些在细胞表面表达GRP 78的细胞，显著下调IRE 1-α、PERK和ATF 6 α依赖性UPR信号传导。相反，促凋亡蛋白GADD 153升高。抗CTD抗体处理还升高了凋亡组分、裂解的PARP-1和Erdj 5。一般而言，观察到所研究的参数的两到三倍效应。这些研究表明，抗CTD抗体通过调节人前列腺癌细胞中的UPR信号传导诱导生长抑制和促凋亡作用。
Receptor-recognized forms of alpha(2)-macroglobulin (alpha M-2*) bind to cancer cell surface GRP78, which functions as a signaling receptor promoting proliferation and survival. Patients with prostate, ovary, and skin cancer may develop auto-antibodies to the alpha M-2* binding site which are receptor agonists whose presence indicates a poor prognosis. By contrast, antibodies directed against the COOH-terminal domain of GPR78 (anti-CTD antibody), are antagonists which down regulate pro-proliferative signaling and upregulate p53. Unfolded protein response (UPR) signaling plays an important role in cell survival and proliferation as well as apoptosis. We, therefore, studied the effect of anti-CTD antibody on UPR signaling in 1-LN and DU-145 prostate cancer cells. Treatment of these cells, which express GRP78 on their cell surface, with this antibody significantly downregulated IRE1-alpha, PERK, and ATF6 alpha-dependent UPR signaling. By contrast, the pro-apoptotic protein GADD153 was elevated. Anti-CTD antibody treatment also elevated apoptotic components, cleaved PARP-1, and Erdj5. In general, a two to threefold effect was observed for the parameters which were studied. These studies suggest that anti-CTD antibody induces growth inhibitory and pro-apoptotic effects by modulating UPR signaling in human prostate cancer cells.