Redox Control of the Senescence Regulator Interleukin-1α and the Secretory Phenotype

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.Background: The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized.Results: Senescent fibroblasts promote tumor invasion through redox/calcium regulation of the cytokine IL-1α.Conclusion: Senescence-associated oxidants and calcium drive the secretory phenotype, altering the microenvironment.Significance: Targeting senescent cells with antioxidant-based therapeutics may restrict inflammation and combat age-related disease progression. 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. Background: The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized. Results: Senescent fibroblasts promote tumor invasion through redox/calcium regulation of the cytokine IL-1α. Conclusion: Senescence-associated oxidants and calcium drive the secretory phenotype, altering the microenvironment. Significance: Targeting senescent cells with antioxidant-based therapeutics may restrict inflammation and combat age-related disease progression.