Human MUC1 carcinoma-associated protein confers resistance to genotoxic anticancer agents.
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.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Jian
J
Ren
Naoki
N
Agata
Dongshu
D
Chen
Yongqing
Y
Li
Wei-hsuan
WH
Yu
Lei
L
Huang
Deepak
D
Raina
Wen
W
Chen
Surender
S
Kharbanda
Donald
D
Kufe
D000941:Antigens / Q000378:metabolism*; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology; D003001:Cloning, Molecular; D045304:Cytochromes c / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D018396:Mucin-1; D009077:Mucins; D020890:Neuregulin-1 / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000941:Antigens; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D006023:Glycoproteins; C060192:MUC1 protein, human; D008562:Membrane Glycoproteins; D018396:Mucin-1; D009077:Mucins; D020890:Neuregulin-1; D021122:Protein Subunits; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002945:Cisplatin