Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells.
Direct targeting of the mucin 1 oncoprotein blocks survival and tumorigenicity of human breast carcinoma cells.
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DOI：
10.1158/0008-5472.can-09-0854
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发表时间：
2009-06-15
期刊：
影响因子：
11.2
通讯作者：
Kufe D
中科院分区：
文献类型：
--
作者：
Raina D;Ahmad R;Joshi MD;Yin L;Wu Z;Kawano T;Vasir B;Avigan D;Kharbanda S;Kufe D
MUC 1癌蛋白在大约90%的人乳腺癌中异常过表达。然而，没有直接抑制MUC 1并诱导乳腺癌细胞死亡的有效药物。我们已经合成了一种MUC 1抑制剂，命名为GO-201，其结合MUC 1胞质结构域并阻断细胞中MUC 1寡聚体的形成。GO-201，而不是一个改变的版本，减弱MUC 1靶向人类乳腺癌细胞的细胞核，破坏氧化还原平衡，并激活DNA损伤反应。G 0 -201还抑制生长并诱导坏死性死亡。相反，MUC 1抑制剂对MUC 1表达无效的细胞或非恶性乳腺上皮细胞没有影响。对携带人乳腺肿瘤异种移植物的裸鼠给予GO-201与致瘤性丧失和广泛坏死相关，导致肿瘤生长的长期消退。这些发现表明，靶向MUC 1癌蛋白在体外和肿瘤模型中有效诱导人乳腺癌细胞死亡。
The MUC1 oncoprotein is aberrantly overexpressed by approximately 90% of human breast cancers. However, there are no effective agents that directly inhibit MUC1 and induce death of breast cancer cells. We have synthesized a MUC1 inhibitor, designated GO-201, that binds to the MUC1 cytoplasmic domain and blocks the formation of MUC1 oligomers in cells. GO-201, and not an altered version, attenuates targeting of MUC1 to the nucleus of human breast cancer cells, disrupts redox balance and activates the DNA damage response. GO-201 also arrests growth and induces necrotic death. By contrast the MUC1 inhibitor has no effect on cells null for MUC1 expression or non-malignant mammary epithelial cells. Administration of GO-201 to nude mice bearing human breast tumor xenografts was associated with loss of tumorigenicity and extensive necrosis that results in prolonged regression of tumor growth. These findings demonstrate that targeting the MUC1 oncoprotein is effective in inducing death of human breast cancer cells in vitro and in tumor models.