ROCK inhibition modulates the senescence-associated secretory phenotype (SASP) in oral keratinocytes

Sven Niklander, Deepti Bandaru, Daniel W. Lambert, Keith D. Hunter

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Senescent cells accumulate in different organs and develop a senescence-associated secretory phenotype (SASP), associated with the development of age-related pathologies. The constitution of the SASP varies among cell types and with the method of senescence induction; nevertheless, there is substantial overlap among SASPs, especially the presence of pro-inflammatory cytokines such as IL-1β, IL-1α, IL-6 and IL-8. These cytokines are highly conserved among SASPs and are implicated in the development of several cancers. Here, we report that ROCK inhibition by Y-27632 reduces levels of IL-1α, IL-1β, IL-6 and IL-8 secreted by senescent normal and dysplastic oral keratinocytes without affecting the permanent cell growth arrest. The data indicate some inflammatory genes downregulated by Y-27632 remain downregulated even after repeated passage in the absence of Y-27632. We propose ROCK kinase inhibition as a novel alternative to current strategies to modulate the inflammatory components of the SASP, without compromising the permanent cell growth arrest. This observation potentially has wide clinical applications, given the involvement of senescence in cancer and a wide range of age-related disease. It also suggests care should be exercised when using Y-27632 to facilitate cell expansion of primary cells, as its effects on gene expression are not entirely reversible.

Original languageEnglish
Pages (from-to)2740-2749
Number of pages10
JournalFEBS Open Bio
Volume10
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • Rho kinase
  • ROCK inhibitors
  • SASP
  • senescence
  • Y-27632

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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