Mitochondrial MKP1 Is a Target for Therapy-Resistant HER2-Positive Breast Cancer Cells
Autor: | Demet Candas, Jian Jian Li, Ming Fan, Chung-Ling Lu, Alexander D. Borowsky, Frank Y. S. Chuang, Colleen A Sweeney |
---|---|
Rok vydání: | 2014 |
Předmět: |
Cancer Research
Pathology Receptor ErbB-2 MAP Kinase Kinase 4 Cell Drug Resistance Apoptosis Mitochondrion Radiation Tolerance ErbB-2 Stem Cell Research - Nonembryonic - Human skin and connective tissue diseases Inner mitochondrial membrane Cancer Membrane Potential Mitochondrial biology Mitochondria Mitochondrial Gene Expression Regulation Neoplastic Protein Transport Cell killing medicine.anatomical_structure Oncology MCF-7 Cells Female Receptor medicine.medical_specialty Oncology and Carcinogenesis Breast Neoplasms Membrane Potential Article Breast cancer Radioresistance Breast Cancer medicine Humans Oncology & Carcinogenesis Radiosensitivity Neoplastic CD44 Dual Specificity Phosphatase 1 HCT116 Cells Stem Cell Research medicine.disease Gene Expression Regulation Drug Resistance Neoplasm biology.protein Cancer research Neoplasm |
Zdroj: | Cancer research, vol 74, iss 24 Candas, D; Lu, CL; Fan, M; Chuang, FYS; Sweeney, C; Borowsky, AD; et al.(2014). Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Research, 74(24), 7498-7509. doi: 10.1158/0008-5472.CAN-14-0844. UC Davis: Retrieved from: http://www.escholarship.org/uc/item/2f58t591 |
ISSN: | 1538-7445 0008-5472 |
Popis: | 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 also detected 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. Cancer Res; 74(24); 7498–509. ©2014 AACR. |
Databáze: | OpenAIRE |
Externí odkaz: |