Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12052-7. doi: 10.1073/pnas.1120437109. Epub 2012 Jul 9.
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.
细胞衰老被广泛认为在肿瘤抑制中发挥关键作用，但调节衰老的分子途径尚不完全清楚。通过使用分泌组蛋白质组学方法，我们发现胰岛素样生长因子结合蛋白 3（IGFBP3）在化疗药物治疗后成为乳腺癌衰老的分泌介质。组织型纤溶酶原激活剂介导的蛋白水解抑制 IGFBP3 的衰老诱导活性，而纤溶酶原激活物抑制剂 1（PAI-1）是衰老的另一种分泌介质，它拮抗 IGFBP3 的活性。我们证明 IGFBP3 是 PAI-1 诱导衰老的关键下游靶标。这些结果表明细胞外分泌蛋白级联在调节细胞衰老中起作用。
