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.
Highlights
The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized
Senescence-associated IL-1␣ Expression Is Regulated by Cellular H2O2—IL-1␣ expression increases as cells near their replicative life span [3,4,5,6], and this elevated expression coincides with an increase in oxidation of the redox-sensitive fluorophore H2DCFDA (Fig. 1, A and B) and supports prior work indicating that senescence is accompanied by increases in steady-state
Because SA increases in IL-1␣ and SS-[H2O2] occur concurrently, we first determined if shifts in SS-[H2O2] influence the expression of SA IL-1␣
Summary
The senescent microenvironment is permissive to disease progression, and the role of oxidants in this process remains uncharacterized. Senescent cells promoted invasion by inducing an epithelialmesenchymal transition, actin reorganization, and cellular polarization of neighboring cancer cells 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-1␣, creating a microenvironment permissive to tumor invasion. Restricting SA oxidative stress or aberrant Ca2ϩ signaling prevents senescent fibroblasts from promoting an invasive phenotype in proximal metastatic cancer epithelial cells. Together, these findings demonstrate how oxidant accumulation and Ca2ϩ deregulation during senescence coordinately influence the SASP and its impact on the tumor microenvironment
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