MADD knock-down enhances doxorubicin and TRAIL induced apoptosis in breast cancer cells

• Published in: PloS one Vol. 8; no. 2; p. e56817
• Main Authors: Turner, Andrea, Li, Liang-Cheng, Pilli, Tania, Qian, Lixia, Wiley, Elizabeth Louise, Setty, Suman, Christov, Konstantin, Ganesh, Lakshmy, Maker, Ajay V, Li, Peifeng, Kanteti, Prasad, Das Gupta, Tapas K, Prabhakar, Bellur S
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15-02-2013; Public Library of Science (PLoS)
• Subjects: Amino Acid Sequence; Analysis; Anthracyclines; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Biology; Biotechnology; Breast cancer; Breast Neoplasms - pathology; Cancer; Cancer cells; Cancer therapies; Carcinoma; Caspase; Caspase-8; Cell death; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Death Domain Receptor Signaling Adaptor Proteins - chemistry; Death Domain Receptor Signaling Adaptor Proteins - deficiency; Death Domain Receptor Signaling Adaptor Proteins - genetics; DNA microarrays; Doxorubicin; Doxorubicin - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Gene Knockdown Techniques; Guanine Nucleotide Exchange Factors - chemistry; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Humans; Immunology; Invasiveness; Kinases; Ligands; MAP kinase; Medicine; Molecular Sequence Data; Mortality; Overexpression; Proteins; Receptors, Death Domain - metabolism; Recruitment; RNA, Small Interfering - genetics; Synergism; Tissues; TNF-Related Apoptosis-Inducing Ligand - pharmacology; TRAIL protein; Tumor cell lines; Tumor necrosis factor-TNF; Illinois; Chicago Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0056817

The Map kinase Activating Death Domain containing protein (MADD) isoform of the IG20 gene is over-expressed in different types of cancer tissues and cell lines and it functions as a negative regulator of apoptosis. Therefore, we speculated that MADD might be over-expressed in human breast cancer tissues and that MADD knock-down might synergize with chemotherapeutic or TRAIL-induced apoptosis of breast cancer cells. Analyses of breast tissue microarrays revealed over-expression of MADD in ductal and invasive carcinomas relative to benign tissues. MADD knockdown resulted in enhanced spontaneous apoptosis in human breast cancer cell lines. Moreover, MADD knockdown followed by treatment with TRAIL or doxorubicin resulted in increased cell death compared to either treatment alone. Enhanced cell death was found to be secondary to increased caspase-8 activation. These data indicate that strategies to decrease MADD expression or function in breast cancer may be utilized to increase tumor cell sensitivity to TRAIL and doxorubicin induced apoptosis.