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

Donald A. McCarthy, Ryan R. Clark, Toni R. Bartling, Mohamed Trebak, J. Andres Melendez

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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 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 epithelialmesenchymal 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.

Original languageEnglish (US)
Pages (from-to)32149-32159
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number45
DOIs
StatePublished - Nov 8 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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