Defect of SIRT1-FoxO3a axis is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated cellular senescence and nematode aging

Abstract

We investigated whether SIRT1 is associated with reactive oxygen species (ROS) accumulation during CK2 downregulation-mediated senescence. SIRT1 overexpression suppressed ROS accumulation, reduced transcription of FoxO3a target genes, and nuclear export and acetylation of FoxO3a, which were induced by CK2 downregulation in HCT116 and MCF-7 cells. Conversely, overexpression of a dominant-negative mutant SIRT1 (H363Y) counteracted decreased ROS levels, increased transcriptional activity of FoxO3a, and increased nuclear import and decreased acetylation of FoxO3a, which were induced by CK2 upregulation. CK2 downregulation destabilized SIRT1 protein via an ubiquitin-proteasome pathway in human cells, whereas CK2 overexpression reduced ubiquitination of SIRT1. Finally, the SIRT1 activator resveratrol attenuated the accumulation of ROS and lipofuscin as well as lifespan shortening, and reduced expression of the DAF-16 target gene sod-3 , which were induced by CK2 downregulation in nematodes. Altogether, this study demonstrates that inactivation of the SIRT1–FoxO3a axis, at least in part, is involved in ROS generation during CK2 downregulation-mediated cellular senescence and nematode aging.

CK2 Down-Regulation Increases the Expression of Senescence-Associated Secretory Phenotype Factors through NF-κB Activation

“…For many years, CK2 was thought to be a constitutive, nonregulated protein kinase [13,14]. Our recent reports have shown that CK2 is downregulated in replicative or oxidative stress-induced senescence in human cells and in nematode aging [15][16][17][18][19][20][21][22][23][24][25][26]. The present study also indicates that LPS downregulates CK2 expression.…”

“…NF-κB is the major regulator that induces the appearance of SASP [8,9]. CK2 down-regulation was previously reported to induce cellular senescence and organism aging [15][16][17][18][19][20][21][22][23][24][25][26], but its relationship to SASP factors is unknown. In this study, we examined the role of CK2 in the expression of SASP.…”

“…elegans has been widely used as a model for exploring the mechanisms underlying aging. CK2 down-regulation in nematodes resulted in reduced longevity and onset of agerelated biomarkers associated with both AGE-1/PI3K-AKT-1/AKT-DAF-16/FoxO and SIR-2.1/SIRT1-DAF-16/FoxO3a axes [25,26]. To investigate the effect of CK2 down-regulation on the expression of SASP factors in worms, the expression of zmp-1 (the ortholog of MMP17 and MMP21), zmp-2 (the ortholog of MMP21), and zmp-3 (the ortholog of MMP1, MMP8, and MMP25) in nematodes treated with kin-10 (the ortholog of CK2β) RNA interference (RNAi) was compared to that in nematodes treated with empty vector control (L4440) RNAi.…”

“…For some experiments, nematodes were treated with triciribine or resveratrol. RNAi experiments were performed with E. coli HT115 cells expressing double-stranded kin-10 RNA, as described previously [25,26].…”

“…In addition, CK2 activity decreased with advancing age in Caenorhabditis elegans, and kin-10 (the ortholog of CK2β) knockdown led to a short lifespan phenotype and induced age-related biomarkers in worms [25]. Agedependent CK2 down-regulation reduces longevity by associating with ROS generation via the AGE-1-AKT-1-DAF-16 pathway [23] and SIRT1-FoxO3a pathway [26] in C. elegans.…”