Plasminogen activator inhibitor 1 - insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence

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 senescenceinducing 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.chemotherapy | isotope-coded affinity tag | protease | protease inhibitor | protein secretion C ellular senescence was originally described as irreversible proliferation arrest that limits the proliferation of human primary cells in culture (1). This phenomenon, "replicative senescence," is caused by progressive shortening of telomeres. In addition, a variety of stressful or oncogenic stimuli can elicit a senescence response. These include DNA damage, oxidative stress, and expression of certain oncogenes such as ras and raf (2, 3). Accumulating evidence suggests that cellular senescence plays important roles in tumor suppression and organismal aging, but how senescence is regulated is largely unknown.In addition to irreversible arrest of proliferation, senescent cells often display common phenotypes such as enlarged, flattened morphology, increased lysosome biogenesis, decreased protein synthesis and degradation, senescence-associated β-gal (SA β-gal) activity, and increased expression of cell cycle inhibitors (2, 3). Further, recent studies have begun to uncover profound alterations in protein secretion from senescent cells, which is collectively called the senescence-associated secretory phenotype (SASP) (4, 5) or senescence-messaging secretome (SMS) (6). These include increased secretion of inflammatory cytokines such as interleukins and chemokines, proteases, and growth regulators. These SASP or SMS factors may recruit immune cells for clearance of senescent cells, affect the architecture or function of surrounding tissues, modulate tumor progression, and contribute to aging and age-related diseases.Most cancer cells express telomerase and do not undergo replicative senescence. However, cancer cells from a variety of tissues undergo senescence upon treatment with chemotherapeutic drugs or ionizing radiation (7,8). Senescent cancer cells are characterized by proliferation arrest, flat and enlarged morphology, and SA β-gal activity, which is similar to the senescence phenotype of primary cells. A previous report demonstrated that naive MCF-7 breast cancer cells undergo senescence upon exposure to conditioned medium from senescent MCF-7 cells induced to senesce by treatment with doxorubicin, a widely used chemotherapeutic drug for...

Autolysosome biogenesis and developmental senescence are regulated by both Spns1 and v-ATPase

“…[25][26][27][28] First, in spns1 hi891/ hi891 fish embryos, our qRT-PCR experiments showed that the expression of glb1 was more than 2-fold enhanced, and serpine1/pai-1 expression, which can also be elevated in cellular and organismal senescence, [29][30][31] became more than 3-fold through 8-fold higher, with the advancing opaque yolk phenotype ( Fig. 6A and B).…”

Plasminogen Activator Inhibitor-1 Suppresses Profibrotic Responses in Fibroblasts from Fibrotic Lungs

“…This probably involves rescue of PAI-1 expression because fibrotic lungs are rich in TGF-␤. Finally, PAI-1 induces replicative senescence in fibroblasts such as MCF-7, IMR-90, and human stromal-derived breast fibroblasts (73)(74)(75). These findings are consistent with ours, showing that PAI-1 is decreased in FL-fibroblasts, which have acquired a highly proliferative/survival phenotype due to hyper-phosphorylation of Akt/PTEN.…”

PAI-1–regulated extracellular proteolysis governs senescence and survival in Klotho mice

“…It was recently demonstrated that the PAI-1-IGFBP-3 cascade promotes stress-induced senescence in human breast fibroblasts (37). Expression levels of IGFBP-3 are increased in response to senescence-inducing stimuli.…”