Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents

• Published in: Cancer cell Vol. 5; no. 2; pp. 163 - 175
• Main Authors: Ren, Jian, Agata, Naoki, Chen, Dongshu, Li, Yongqing, Yu, Wei-hsuan, Huang, Lei, Raina, Deepak, Chen, Wen, Kharbanda, Surender, Kufe, Donald
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2004
• Subjects: Antigens - metabolism; Antigens, Neoplasm; Antineoplastic Agents - pharmacology; Apoptosis - physiology; Apoptosis Regulatory Proteins; Caspase 3; Caspases - metabolism; Cisplatin - pharmacology; Cloning, Molecular; Cytochromes c - metabolism; DNA Damage - physiology; Drug Resistance, Neoplasm - physiology; Flow Cytometry; Glycoproteins - metabolism; Membrane Glycoproteins - metabolism; Mitochondria - metabolism; MUC1 gene; Mucin-1; Mucins; Neuregulin-1 - pharmacology; Protein Subunits - metabolism; RNA, Small Interfering - metabolism; siRNA; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/S1535-6108(04)00020-0

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.