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

Abstract

Senescent cells secrete pro-inflammatory factors, and a hallmark feature of senescence is senescence-associated secretory phenotype (SASP). The aim of this study is to investigate the protein kinase CK2 (CK2) effects on SASP factors expression in cellular senescence and organism aging. Here CK2 down-regulation induced the expression of SASP factors, including interleukin (IL)-1β, IL-6, and matrix metalloproteinase (MMP) 3, through the activation of nuclear factor-κB (NF-κB) signaling in MCF-7 and HCT116 cells. CK2 down-regulation-mediated SIRT1 inactivation promoted the degradation of inhibitors of NF-κB (IκB) by activating the AKT-IκB kinase (IKK) axis and increased the acetylation of lysine 310 on RelA/p65, an important site for the activity of NF-κB. kin-10 (the ortholog of CK2β) knockdown increased zmp-1, -2, and -3 (the orthologs of MMP) expression in nematodes, but AKT inhibitor triciribine and SIRT activator resveratrol significantly abrogated the increased expression of these genes. Finally, antisense inhibitors of miR-186, miR-216b, miR-337-3p, and miR-760 suppressed CK2α down-regulation, activation of the AKT-IKK-NF-κB axis, RelA/p65 acetylation, and expression of SASP genes in cells treated with lipopolysaccharide. Therefore, this study indicated that CK2 down-regulation induces the expression of SASP factors through NF-κB activation, which is mediated by both activation of the SIRT1-AKT-IKK axis and RelA/p65 acetylation, suggesting that the mixture of the four miRNA inhibitors can be used as anti-inflammatory agents.

Long Non-Coding RNA KCNQ1OT1 Regulates Protein Kinase CK2 Via miR-760 in Senescence and Calorie Restriction

“…KCNQ1OT1 knockdown increas ROS production, as indicated by the right shift in fluorescence during flow cytome (Figure 2B). It was previously reported that CK2 downregulation induces SASP expr sion [20] and ROS generation [18]. Ectopic expression of CK2α abrogated the induction SASP factor expression and ROS generation, mediated by KCNQ1OT1 downregulat (Figure 2A and B).…”

“…Because treatment with LPS causes cellular senescence by downregulating CK2α [20], it was tested whether LPS downregulated KCNQ1OT1 expression. Treatment with LPS (6 µg/µL) reduced the transcript levels of CK2α and KCNQ1OT1 in human cancer cells (Figure 3A).…”

“…Previous studies identified the protein kinase CK2 (CK2), composed of two catalytic (α and/or α ) subunits and two regulatory β subunits, as a senescence regulator. CK2 inhibition triggers the expression of several senescence markers, including senescenceassociated β-galactosidase (SA-β-gal) activity [16], p53-p21 Cip1/WAF1 axis activation [17], reactive oxygen species (ROS) production [18], senescence-associated heterochromatin foci (SAHF) formation [19], and senescence-associated secretory phenotype (SASP) expression [20]. miR-186, miR-216b, miR-337-3p, and miR-760 promote cellular senescence by inhibiting CK2α [21,22].…”

Relieving Cellular Energy Stress in Aging, Neurodegenerative, and Metabolic Diseases, SIRT1 as a Therapeutic and Promising Node

“…In addition, CK2-mediated phosphorylation of SIRT1 at the Ser164 site inhibits its nuclear localization and promotes the progress of non-alcoholic fatty liver (Choi et al, 2017 ), which provides evidence that SIRT1 is involved in the improvement of metabolic diseases. However, A recent study showed that in senescent cells, down-regulation of CK2 can mediate the inactivation of SIRT1, thus activating NF-KB and inducing the expression of senescence-associated secretory phenotype (SASP) factors (Song and Bae, 2021 ). This suggests that SIRT1 accepts negative regulation from CK2, but more evidence is needed to guide us to accurately understand the role of CK2 in different pathological models.…”

Editorial for the Special Issue “Molecular Bases of Senescence”

“…However, senescent cells secrete pro-inflammatory factors through a secretory phenotype associated with senescence that is very particular to this cellular situation. In the paper of Song and Bae [5], the effects of protein kinase CK2 on the expression of some of the factors involved in the senescence-associated secretory phenotype, including interleukin IL-1β, IL-6, and MMP3, were investigated. The data presented here indicate that during the aging process, an enhancement of the senescence-associated secretory phenotype (SASP) occurs through down-regulation of CK2 via dysregulation of NF-κB (IκB) transcription factors and the AKT-IκB kinase axis.…”