Plasminogen activator inhibitor 1--insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence.
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.
Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
David J
DJ
Elzi
Yanlai
Y
Lai
Meihua
M
Song
Kevin
K
Hakala
Susan T
ST
Weintraub
Yuzuru
Y
Shiio
D000704:Analysis of Variance; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D003470:Culture Media / Q000737:chemistry; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013312:Stress, Physiological / Q000502:physiology*; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D001616:beta-Galactosidase
D003470:Culture Media; D017931:DNA Primers; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; C051321:SERPINE1 protein, human; D004317:Doxorubicin; D001616:beta-Galactosidase; D010959:Tissue Plasminogen Activator