Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype |
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Authors: | Donald A McCarthy Ryan R Clark Toni R Bartling Mohamed Trebak J Andres Melendez |
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Institution: | From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203 |
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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 Ca2+ levels caused an increase in IL-1α expression and processing. The increase in intracellular Ca2+ 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. Ca2+ 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 Ca2+ 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 Ca2+ homeostasis modulate the inflammatory phenotype through the regulation of the SASP initiator IL-1α, creating a microenvironment permissive to tumor invasion. |
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Keywords: | Antioxidants Calcium Calpain Cell Invasion Cellular Senescence Epithelial-Mesenchymal Transition Hydrogen Peroxide Interleukin Redox Regulation |
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