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J Biol Chem. 2013 Nov 8;288(45):32149-59. doi: 10.1074/jbc.M113.493841. Epub 2013 Sep 23.

Redox control of the senescence regulator interleukin-1α and the secretory phenotype.

Author information

1
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203.

Abstract

Senescent cells accumulate in aged tissue and are causally linked to age-associated tissue degeneration. These non-dividing, metabolically active cells are highly secretory and alter tissue homeostasis, creating an environment conducive to metastatic disease progression. IL-1α is a key senescence-associated (SA) proinflammatory cytokine that acts as a critical upstream regulator of the SA secretory phenotype (SASP). We established that SA shifts in steady-state H2O2 and intracellular Ca(2+) levels caused an increase in IL-1α expression and processing. The increase in intracellular Ca(2+) promoted calpain activation and increased the proteolytic cleavage of IL-1α. Antioxidants and low oxygen tension prevented SA IL-1α expression and restricted expression of SASP components IL-6 and IL-8. Ca(2+) chelation or calpain inhibition prevented SA processing of IL-1α and its ability to induce downstream cytokine expression. Conditioned medium from senescent cells treated with antioxidants or Ca(2+) chelators or cultured in low oxygen markedly reduced the invasive capacity of proximal metastatic cancer cells. In this paracrine fashion, senescent cells promoted invasion by inducing an epithelial-mesenchymal transition, actin reorganization, and cellular polarization of neighboring cancer cells. Collectively, these findings demonstrate how SA alterations in the redox state and Ca(2+) homeostasis modulate the inflammatory phenotype through the regulation of the SASP initiator IL-1α, creating a microenvironment permissive to tumor invasion.

KEYWORDS:

Antioxidants; Calcium; Calpain; Cell Invasion; Cellular Senescence; Epithelial-Mesenchymal Transition; Hydrogen Peroxide; Interleukin; Redox Regulation

PMID:
24062309
PMCID:
PMC3820855
DOI:
10.1074/jbc.M113.493841
[Indexed for MEDLINE]
Free PMC Article
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