人MUC1癌相关蛋白赋予对基因毒性抗癌药物的抗性。
Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents.
作者信息
Ren Jian, Agata Naoki, Chen Dongshu, Li Yongqing, Yu Wei-hsuan, Huang Lei, Raina Deepak, Chen Wen, Kharbanda Surender, Kufe Donald
机构信息
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
出版信息
Cancer Cell. 2004 Feb;5(2):163-75. doi: 10.1016/s1535-6108(04)00020-0.
Abstract
The MUC1 transforming protein is overexpressed by most human carcinomas. The present studies demonstrate that the MUC1 C-terminal subunit (MUC1 C-ter) localizes to mitochondria in HCT116/MUC1 colon carcinoma cells and that heregulin stimulates mitochondrial targeting of MUC1 C-ter. We also show that MUC1 attenuates cisplatin-induced (1) release of mitochondrial apoptogenic factors, (2) activation of caspase-3, and (3) induction of apoptosis. Moreover, knockdown of MUC1 expression in A549 lung and ZR-75-1 breast carcinoma cells by MUC1siRNA was associated with increased sensitivity to genotoxic drugs in vitro and in vivo. These findings indicate that MUC1 attenuates the apoptotic response to DNA damage and that this oncoprotein confers resistance to genotoxic anticancer agents.
摘要
MUC1转化蛋白在大多数人类癌症中过度表达。目前的研究表明，MUC1 C末端亚基（MUC1 C-ter）定位于HCT116/MUC1结肠癌细胞的线粒体中，并且这里调节蛋白刺激MUC1 C-ter的线粒体靶向。我们还表明，MUC1减弱顺铂诱导的（1）线粒体凋亡因子的释放，（2）半胱天冬酶-3的激活，以及（3）细胞凋亡的诱导。此外，通过MUC1 siRNA敲低A549肺癌细胞和ZR-75-1乳腺癌细胞中的MUC1表达与体外和体内对基因毒性药物的敏感性增加相关。这些发现表明，MUC1减弱对DNA损伤的凋亡反应，并且这种癌蛋白赋予对基因毒性抗癌剂的抗性。
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