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PMID: 14998492 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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

Cancer cell ·Vol. 5 ·No. 2 ·2004-02-00 ·Pages 163-75

Ren J, Agata N, Chen D, Li Y, Yu WH, Huang L, Raina D, Chen W, Kharbanda S, Kufe D

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.

MeSH Terms
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 Mucin-1 Mucins Neuregulin-1/pharmacology Protein Subunits/metabolism RNA, Small Interfering/metabolism TNF-Related Apoptosis-Inducing Ligand Tumor Cells, Cultured Tumor Necrosis Factor-alpha/metabolism
Chemicals
Antigens Antigens, Neoplasm Antineoplastic Agents Apoptosis Regulatory Proteins Glycoproteins MUC1 protein, human Membrane Glycoproteins Mucin-1 Mucins Neuregulin-1 Protein Subunits RNA, Small Interfering TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Tumor Necrosis Factor-alpha Cytochromes c CASP3 protein, human Caspase 3 Caspases Cisplatin
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Ren Jian
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Agata Naoki
Chen Dongshu
Li Yongqing
Yu Wei-hsuan
Huang Lei
Raina Deepak
Chen Wen
Kharbanda Surender
Kufe Donald
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1535-6108
DOI
10.1016/s1535-6108(04)00020-0
Published
2004-02-00
Pages
163-75
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC4217165
Subset
IM
Grants
NCI NIH HHS · R01 CA029431 · United States
NCI NIH HHS · R01 CA097098 · United States
NCI NIH HHS · CA29431 · United States
NCI NIH HHS · CA97098 · United States
Corrections
CommentIn
PMID: 14998483
External Links
PubMed source DOI: 10.1016/s1535-6108(04)00020-0 PMC Full Text View journal details
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