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 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.
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203.
Donald A
DA
McCarthy
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203.
Ryan R
RR
Clark
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203.
Toni R
TR
Bartling
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203.
Mohamed
M
Trebak
From the College of Nanoscale Science and Engineering, State University of New York, Albany, New York 12203. Electronic address: jmelendez@albany.edu.
J Andres
JA
Melendez
D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D019899:Paracrine Communication / Q000502:physiology; D059748:Proteolysis; D059016:Tumor Microenvironment
C508606:CXCL8 protein, human; C508584:IL1A protein, human; C508600:IL6 protein, human; D053582:Interleukin-1alpha; D015850:Interleukin-6; D016209:Interleukin-8; D009363:Neoplasm Proteins; D016877:Oxidants; D006861:Hydrogen Peroxide; D002154:Calpain; D002118:Calcium
Antioxidants; Calcium; Calpain; Cell Invasion; Cellular Senescence; Epithelial-Mesenchymal Transition; Hydrogen Peroxide; Interleukin; Redox Regulation