Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells.
Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells.
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DOI：
10.1158/0008-5472.can-14-0844
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发表时间：
2014-12-15
期刊：
影响因子：
11.2
通讯作者：
Li JJ
中科院分区：
文献类型：
--
作者：
Candas D;Lu CL;Fan M;Chuang FY;Sweeney C;Borowsky AD;Li JJ
MAPK磷酸酶MKP 1（DUSP 1）在许多人类癌症中过表达，包括化学抗性和放射抗性乳腺癌细胞，但其在这些环境中的功能贡献尚不清楚。在这里，我们报告说，细胞照射后，MKP 1易位到线粒体，在那里它防止通过限制积累的应激激酶JNK的磷酸化活性形式的凋亡诱导。照射后线粒体MKP 1水平增加发生在线粒体内膜空间。值得注意的是，由线粒体MKP 1调节的细胞存活负责在HER 2过表达乳腺癌细胞中赋予放射抗性，这是由于MKP 1在HER 2激活的RAF-MEK-ERK途径中充当主要下游效应子的事实。在临床上，我们记录了MKP 1表达仅在HER 2阳性乳腺肿瘤中，相对于来自相同患者的正常相邻组织。在从长期放射治疗后的放射抗性乳腺癌细胞群中分离的经放射的HER 2阳性乳腺癌干细胞样细胞（HER 2 +/CD 44 +/CD 24 −/低）中也检测到MKP 1过表达。MKP 1沉默降低了这些干细胞样细胞的克隆存活率并增强了放射敏感性。MKP 1和HER 2的联合抑制增强了乳腺癌中的细胞杀伤。总之，我们的研究结果确定了乳腺肿瘤耐药的新机制，并揭示了MKP 1作为放射增敏的新治疗靶点。
The MAPK phosphatase MKP1 (DUSP1) is overexpressed in many human cancers, including chemoresistant and radioresistant breast cancer cells, but its functional contributions in these settings are unclear. Here we report that after cell irradiation MKP1 translocates into mitochondria, where it prevents apoptotic induction by limiting accumulation of phosphorylated active forms of the stress kinase JNK. Increased levels of mitochondrial MKP1 after irradiation occurred in the mitochondrial inner membrane space. Notably, cell survival regulated by mitochondrial MKP1 was responsible for conferring radioresistance in HER2-overexpressing breast cancer cells, due to the fact that MKP1 serves as a major downstream effector in the HER2-activated RAF-MEK-ERK pathway. Clinically, we documented MKP1 expression exclusively in HER2-positive breast tumors, relative to normal adjacent tissue from the same patients. MKP1 overexpression was detected also in irradiated HER2-positive breast cancer stem-like cells (HER2+/CD44+/CD24−/low) isolated from a radioresistant breast cancer cell population after long-term radiation treatment. MKP1 silencing reduced clonogenic survival and enhanced radiosensitivity in these stem-like cells. Combined inhibition of MKP1 and HER2 enhanced cell killing in breast cancer. Together, our findings identify a new mechanism of resistance in breast tumors and reveal MKP1 as a novel therapeutic target for radiosensitization.