Inactivation of the FoxO3a transcription factor is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated senescence in human colon cancer and breast cancer cells

Park, Seong-Yeol; Bae, Young‐Seuk

doi:10.1016/j.bbrc.2016.07.106

Cited by 15 publications

(20 citation statements)

References 16 publications

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“…Thus, we conclude that CK2 functions between AKT-1 and DAF-16 in worms. This is not consistent with our previous report that CK2 acts upstream of the AKT in human colon cancer cells [14, 15]. Although we currently cannot explain this discrepancy, we hypothesize that CK2 may function at different stages of the IIS pathway depending on the organism type (e.g., invertebrate or vertebrate).…”

Section: Discussioncontrasting

confidence: 99%

“…Since SOD-3/MnSOD detoxifies ROS [34] and DOD-11/sorbitol dehydrogenase reduces the nicotinamide adenine dinucleotide (NAD + ) level in the conversion of sorbitol to fructose [35], our observations suggest that CK2 inhibition-mediated downregulation of SOD-3 and DOD-11 may cause an imbalance between ROS production and removal in C. elegans . These results are consistent with our previous report indicating that CK2 inhibition stimulates ROS production through inhibition of FoxO3a activity in human cells [15]. The present study found that kin-10 knockdown decreased the transcriptional activity of DAF-16 on the mtl-1 promoters, but it enhanced that of DAF-16 on the dod-8 promoter in worms.…”

Section: Discussionsupporting

confidence: 94%

“…In addition, CK2 inhibition induces premature senescence through the ROS-p53-p21 Cip1/WAF1 pathway in human cells such as lung fibroblast IMR-90, colon cancer HCT116, and breast cancer MCF-7cells [11–15]. In this study, we examined whether CK2 modulated longevity in C. elegans .…”

Section: Discussionmentioning

confidence: 99%

“…Reactive oxygen species (ROS) production and p53 acetylation by downregulation of NAD + -dependent protein deacetylase SIRT1 serve as upstream activators of p53 stabilization in senescent cells due to CK2 inhibition [12, 13]. Inhibition of PI3K, AKT, and mammalian target of rapamycin (mTOR), as well as ectopic expression of FoxO3a, attenuated ROS production and senescence in CK2-downregulated cells, indicating that the PI3K-AKT-mTOR pathway as well as FoxO3a are involved in CK2 inhibition-mediated ROS generation [14, 15]. …”

Section: Introductionmentioning

confidence: 99%

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Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

et al. 2017

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Studies show that a decrease in protein kinase CK2 (CK2) activity is associated with cellular senescence. However, the role of CK2 in organism aging is still poorly understood. Here, we investigated whether protein kinase CK2 (CK2) modulated longevity in Caenorhabditis elegans. CK2 activity decreased with advancing age in the worms. Knockdown of kin-10 (the ortholog of CK2β) led to a short lifespan phenotype and induced age-related biomarkers, including retardation of locomotion, decreased pharyngeal pumping rate, increased lipofuscin accumulation, and reduced resistance to heat and oxidative stress. The long lifespan of age-1 and akt-1 mutants was significantly suppressed by kin-10 RNAi, suggesting that CK2 acts downstream of AGE-1 and AKT-1. Kin-10 knockdown did not further shorten the short lifespan of daf-16 mutant worms but either decreased or increased the transcriptional activity of DAF-16 depending on the promoters of the target genes, indicating that CK2 is an upstream regulator of DAF-16 in C. elegans. Kin-10 knockdown increased production of reactive oxygen species (ROS) in the worms. Finally, the ROS scavenger N-acetyl-L-cysteine significantly counteracts the lifespan shortening and lipofuscin accumulation induced by kin-10 knockdown. Therefore, the present results suggest that age-dependent CK2 downregulation reduces longevity by associating with both ROS generation and the AGE-1-AKT-1-DAF-16 pathway in C. elegans.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

et al. 2017

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“…This is consistent with the fact that PLD and CK2 positively regulate each other for the following reasons. First, CK2 downregulation, like PLD downregulation, induces cellular senescence via activating the ROS-p53-p21 Cip1/WAF1 pathway by downregulating FoxO3a in human cells 29 – 32 . Second, enhanced CK2 activity strongly represses PLD2 knockdown-mediated senescence in human cells, and vice versa 14 .…”

Section: Discussionmentioning

confidence: 99%

Role of phospholipase D in the lifespan of Caenorhabditis elegans

Park

Lee

et al. 2018

Exp Mol Med

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We have previously shown that phospholipase D (PLD) downregulation accelerates cellular senescence, which is widely believed to play an important role in aging, by stimulating reactive oxygen species (ROS) accumulation in human cells. In this study, we examined the role of PLD in aging using the nematode Caenorhabditis elegans. The mRNA level of pld-1 was found to be inversely correlated with aging. RNAi-mediated knockdown of pld-1 expression in nematodes enhanced ROS and lipofuscin accumulation and decreased lifespan, motility, and resistance to stress compared to that in nematodes treated with control RNAi. Pld-1 knockdown repressed the long lifespan of age-1 and akt-1 mutants but did not further reduce the short lifespan of daf-16 mutants, suggesting that PLD functions between AKT-1 and DAF-16. The ROS scavenger N-acetyl-L-cysteine, a PLD effector phosphatidic acid and a possible CK2 activator spermidine attenuated the lifespan shortening and age-related biomarkers triggered by pld-1 knockdown. Pld-1 RNAi downregulated the expression of DAF-16 target genes such as sod-3, dod-11, and mtl-1 in nematodes. In human cells, furthermore, PLD2 downregulation decreased the transcription of FoxO3a target genes (Cu/ZnSOD, MnSOD, catalase, thioredoxin-2, and peroxiredoxin-5), whereas ectopic PLD2 expression elevated the mRNA levels of these antioxidant genes. Taken together, these results indicated that PLD downregulation shortens longevity and induces age-related biomarkers through ROS accumulation by inhibiting the DAF-16/FoxO3a pathway in nematodes.

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Protein kinase C downregulation induces senescence via FoxO3a inhibition in HCT116 and HEK293 cells

Park

Lee

Bae

2017

Biochemical and Biophysical Research Communications

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Inactivation of the FoxO3a transcription factor is associated with the production of reactive oxygen species during protein kinase CK2 downregulation-mediated senescence in human colon cancer and breast cancer cells

Cited by 15 publications

References 16 publications

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

Downregulation of protein kinase CK2 activity induces age-related biomarkers inC. elegans

Role of phospholipase D in the lifespan of Caenorhabditis elegans

Protein kinase C downregulation induces senescence via FoxO3a inhibition in HCT116 and HEK293 cells

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