S100A13 promotes senescence-associated secretory phenotype and cellular senescence via modulation of non-classical secretion of IL-1α.

Yuanyuan Su,Chenzhong Xu,Guodong Li,Yao Liang,Zhaomeng Sun,Jun Chen,Tanjun Tong

doi:10.18632/aging.101760

Abstract

Senescent cells display the senescence-associated secretory phenotype (SASP) which plays important roles in cancer, aging, etc. Cell surface-bound IL-1α is a crucial SASP factor and acts as an upstream regulator to induce NF-κB activity and subsequent SASP genes transcription. IL-1α exports to cell surface via S100A13 protein-dependent non-classical secretory pathway. However, the status of this secretory pathway during cellular senescence and its role in cellular senescence remain unknown. Here, we show that S100A13 is up-regulated in various types of cellular senescence. S100A13 overexpression increases cell surface-associated IL-1α level, NF-κB activity and subsequent multiple SASP genes induction, whereas S100A13 knockdown has an opposite role. We also exhibit that Cu2+ level is elevated during cellular senescence. Lowering Cu2+ level decreases cell surface-bound IL-1α level, NF-κB activity and SASP production. Moreover, S100A13 overexpression promotes oncogene Ras-induced cell senescence (Ras OIS), Doxorubicin-induced cancer cell senescence (TIS) and replicative senescence, while impairment of non-classical secretory pathway of IL-1α delays cellular senescence. In addition, intervention of S100A13 affects multiple SASP and cellular senescence mediators including p38, γ-H2AX, and mTORC1. Taken together, our findings unveil a critical role of the non-classical secretory pathway of IL-1α in cellular senescence and SASP regulation.

Highlights

Cellular senescence is a permanent cell cycle arrest state in response to various intracellular and extracellular stimuli such as telomere erosion because of repeated cell division, DNA damage, oxidative stress, and oncogenes including Ras or Myc activation, etc [1]
Agreed with previous report [22], chronically treated HCT116 cells with low dose of Dox induced NF-κB activation and subsequent IL-6/IL-8 mRNAs production, as well as p21 up-regulation when compared to the untreated cells (Figure 1A, 1B), which indicated that HCT116 cells underwent senescence and developed senescence-associated secretory phenotype (SASP)
NF-κB is a downstream target of IL-1R signaling activated by cell surface-bound IL-1α in various types of cell senescence [11], we examined whether S100A13 regulated NF-κB activity through modulation of IL-1α secretion during cell senescence

Summary

Introduction

Cellular senescence is a permanent cell cycle arrest state in response to various intracellular and extracellular stimuli such as telomere erosion because of repeated cell division (replicative senescence), DNA damage, oxidative stress, and oncogenes including Ras or Myc activation, etc [1]. One hallmark of senescence is that senescent cells secret multiple pro-inflammatory cytokines, chemokines, growth factors, and other proteins which is referred to as senescence-associated secretory phenotype (SASP) [1]. The SASP has been shown to have contextdependent pleiotropic biological and physiological functions. SASP has tumor suppressive roles either via cell autonomous mechanism to reinforce cell senescence [2], or using ‘immune surveillance’ mechanism via cell non-autonomous fashion [3]. The SASP factors assist tissue repair, embryonic development, as well as in vivo cell reprogramming through paracrine manner [4,5,6]. The mounting evidences show that SASP factors can promote tumor growth and invasion, and contribute to many age-related diseases and aging in late-life [7]

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