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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2004-3-17
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pubmed:abstractText |
Insulin-like growth factor-binding protein (IGFBP)-3 has been shown to potently inhibit cell proliferation in various cell systems. However, the specific mechanisms involved in the antiproliferative action of IGFBP-3 have yet to be elucidated. In the present study, we demonstrate that IGFBP-3 induces apoptosis in an insulin-like growth factor (IGF)-independent manner through the activation of caspases involved in a death receptor-mediated pathway in MCF-7 human breast cancer cells. Induction of IGFBP-3 using an ecdysone-inducible expression system inhibited DNA synthesis in an IGF-IGF receptor axis-independent fashion and resulted in the subsequent induction of apoptosis and an increase in caspase activity. Similar results were obtained when cells were transfected with GGG-IGFBP-3, an IGFBP-3 mutant unable to bind IGFs, corroborating the IGF-independent action of IGFBP-3. Additional caspase activity studies and immunoblot analyses using specific caspase substrates and/or caspase inhibitors revealed that the growth-inhibitory effect of IGFBP-3 results mainly from its induction of apoptosis (in particular, activation of caspase-8 and -7). Analyses of caspase-9 activity and release of cytochrome c into the cytosol confirmed that the mitochondria-mediated pathway is not involved. Taken together, these results show that IGFBP-3 expression leads to the induction of apoptosis through the activation of caspases involved in a death receptor-mediated pathway and that IGFBP-3 functions as a negative regulator of breast cancer cell growth, independent of the IGF-IGF receptor axis.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochromes c,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Ecdysone,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor Binding...,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor I,
http://linkedlifedata.com/resource/pubmed/chemical/Insulin-Like Growth Factor II,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 1,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, IGF Type 2,
http://linkedlifedata.com/resource/pubmed/chemical/Tumor Necrosis Factor-alpha
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pubmed:status |
MEDLINE
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pubmed:month |
Mar
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pubmed:issn |
0008-5472
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
15
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pubmed:volume |
64
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
2229-37
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15026367-Antineoplastic Agents,
pubmed-meshheading:15026367-Apoptosis,
pubmed-meshheading:15026367-Breast Neoplasms,
pubmed-meshheading:15026367-Caspases,
pubmed-meshheading:15026367-Cell Division,
pubmed-meshheading:15026367-Cytochromes c,
pubmed-meshheading:15026367-Cytosol,
pubmed-meshheading:15026367-DNA, Neoplasm,
pubmed-meshheading:15026367-Ecdysone,
pubmed-meshheading:15026367-Enzyme Inhibitors,
pubmed-meshheading:15026367-Enzyme-Linked Immunosorbent Assay,
pubmed-meshheading:15026367-Humans,
pubmed-meshheading:15026367-Insulin-Like Growth Factor Binding Protein 3,
pubmed-meshheading:15026367-Insulin-Like Growth Factor I,
pubmed-meshheading:15026367-Insulin-Like Growth Factor II,
pubmed-meshheading:15026367-Mitochondria,
pubmed-meshheading:15026367-Receptor, IGF Type 1,
pubmed-meshheading:15026367-Receptor, IGF Type 2,
pubmed-meshheading:15026367-Signal Transduction,
pubmed-meshheading:15026367-Transfection,
pubmed-meshheading:15026367-Tumor Cells, Cultured,
pubmed-meshheading:15026367-Tumor Necrosis Factor-alpha
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pubmed:year |
2004
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pubmed:articleTitle |
Insulin-like growth factor-binding protein 3 induces caspase-dependent apoptosis through a death receptor-mediated pathway in MCF-7 human breast cancer cells.
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pubmed:affiliation |
Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.
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