Abstract
Cellular senescence is widely believed to play a key role in tumor suppression, but the molecular pathways that regulate senescence are only incompletely understood. By using a secretome proteomics approach, we identified insulin-like growth factor binding protein 3 (IGFBP3) as a secreted mediator of breast cancer senescence upon chemotherapeutic drug treatment. The senescence-inducing activity of IGFBP3 is inhibited by tissue-type plasminogen activator-mediated proteolysis, which is counteracted by plasminogen activator inhibitor 1 (PAI-1), another secreted mediator of senescence. We demonstrate that IGFBP3 is a critical downstream target of PAI-1-induced senescence. These results suggest a role for an extracellular cascade of secreted proteins in the regulation of cellular senescence.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Analysis of Variance
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Cell Line, Tumor
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Cellular Senescence / physiology*
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Culture Media / chemistry
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DNA Primers / genetics
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Doxorubicin / pharmacology
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Enzyme-Linked Immunosorbent Assay
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Fluorescent Antibody Technique
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Humans
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Immunoblotting
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Immunohistochemistry
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Insulin-Like Growth Factor Binding Protein 3 / metabolism*
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Neoplasms / physiopathology
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Plasminogen Activator Inhibitor 1 / metabolism*
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Proteolysis / drug effects*
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Proteomics / methods
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RNA, Small Interfering / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Stress, Physiological / physiology*
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Tissue Plasminogen Activator / metabolism
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Tissue Plasminogen Activator / pharmacology*
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Tumor Cells, Cultured
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beta-Galactosidase
Substances
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Culture Media
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DNA Primers
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IGFBP3 protein, human
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Insulin-Like Growth Factor Binding Protein 3
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Plasminogen Activator Inhibitor 1
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RNA, Small Interfering
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SERPINE1 protein, human
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Doxorubicin
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beta-Galactosidase
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Tissue Plasminogen Activator