| 概要： |
Cellular senescence is widely believed to play key roles in tumor suppression, but signaling pathways mediating senescence are only incompletely understood. By analyzing the proteins secreted from senescent cells, we identified two novel mediators of senescence.
1) Employing the quantitative proteomic analysis of secreted proteins, we determined that the Wnt signaling inhibitor SFRP1 (Secreted Frizzled-related Protein 1) is over-secreted from IMR-90 human primary fibroblasts induced to senesce by DNA damage. Downregulation of SFRP1 by shRNA or by neutralizing antibody inhibited DNA damage-induced senescence while recombinant SFRP1 by itself was able to induce senescence, indicating that SFRP1 is necessary and sufficient for senescence induction. SFRP1 induced senescence through inhibition of Wnt signaling and activation of the Rb pathway. Interestingly, cancer-associated SFRP1 mutants were defective for senescence induction.
2) In addition to normal cells, cancer cells also undergo senescence upon chemotherapeutic drug treatment. We observed that non-senescent MCF-7 breast cancer cells become senescent upon addition of the conditioned medium from senescent MCF-7 cells induced to senesce by doxorubicin treatment, which suggested the presence of secreted mediator(s) of senescence. Using quantitative secretome proteomics, we identified IGFBP3 (insulin-like growth factor binding protein 3) as a mediator of doxorubicin-induced senescence. Further, we found that IGFBP3 can be cleaved and inactivated by t-PA (tissue-type plasminogen activator). t-PA is negatively regulated by another known secreted mediator of senescence, PAI-1 (plasminogen activator inhibitor 1). We uncovered a cascade whereby PAI-1 induces senescence through the elevation of IGFBP3 levels.
These studies identified extracellular components of senescence signaling. Senescence mediators secreted from senescent cells may amplify the senescence response and provide a non-cell autonomous tumor suppression mechanism in precancerous cells as well as in chemotherapy-treated tumor cells. |
