Abstract
Evasion of apoptosis plays a key role in cancer development, drug resistance, and recurrence. The BRCA1 locus product protein BRCA1-IRIS is overexpressed in several cisplatin-resistant ovarian cancer cell lines, but its relationship to resistance is uncertain. Here, we show that in human ovarian surface epithelial (HOSE) cells, overexpression of BRCA1-IRIS triggers expression of the antiapoptotic protein survivin. Negative modulation of phosphatidylinositol 3-kinase (PI3K) signaling or AKT silencing reduced survivin expression in this setting. Conversely, silencing BRCA1-IRIS in ovarian cancer cell lines derepressed PTEN expression along with the antiapoptotic AKT targets FOXO1 and FOXO3a, suppressing survivin expression. Cisplatin (≤50 μmol/L) exposure was sufficient to activate expression of the BRCA1-IRIS-AKT-survivin cascade in HOSE cells, whereas under similar conditions cisplatin failed to induce apoptosis in ovarian cancer cell lines expressing this regulatory cascade. Mechanistic investigations indicated that BRCA1-IRIS triggers survivin expression through a PI3K/AKT-dependent pathway involving NF-κB, but also through a PI3K/AKT-independent pathway involving PTEN, FOXO1, and FOXO3a. Our findings indicate how BRCA1-IRIS overexpression prevents chemotherapy-induced cell death by upregulating expression of survivin, and they highlight this regulatory cascade as a candidate focus to improve treatment of advanced drug-resistant ovarian cancers.
©2010 AACR.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis
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BRCA1 Protein / antagonists & inhibitors
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism*
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Blotting, Western
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Caspases / metabolism
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Cell Cycle
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Cell Line, Tumor
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Cisplatin / pharmacology*
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Drug Resistance, Neoplasm*
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Female
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism
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Humans
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / metabolism*
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Ovarian Neoplasms / pathology
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism
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Phosphatidylinositol 3-Kinase / genetics
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Phosphatidylinositol 3-Kinase / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Messenger / genetics
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RNA, Small Interfering / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Survivin
Substances
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Antineoplastic Agents
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BIRC5 protein, human
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BRCA1 Protein
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BRCA1 protein, human
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FOXO1 protein, human
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FOXO3 protein, human
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Forkhead Box Protein O1
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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Inhibitor of Apoptosis Proteins
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Microtubule-Associated Proteins
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NF-kappa B
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RNA, Messenger
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RNA, Small Interfering
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Survivin
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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PTEN Phosphohydrolase
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PTEN protein, human
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Caspases
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Cisplatin