SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation

Zhao, Gexin; Wang, Hui; Xu, Caimin; Wang, Pan; Chen, Jun; Wang, Pengfeng; Sun, Zhaomeng; Su, Yuanyuan; Wang, Zhao; Han, Limin; Tong, Tanjun

doi:10.18632/aging.101038

Cited by 27 publications

(21 citation statements)

References 56 publications

(59 reference statements)

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“…p27 is a regulator of cyclin-dependent kinases (CDK); when bound, p27 inactivates CDKs and induces cell cycle arrest at G1, S, or G2 phases. 33 Our data demonstrated that siRNA knockdown of p27 rescued GBM cells from matrine-induced senescence and implicate p27 as a critical molecule mediating matrine-induced cellular senescence. Thus, we were able to demonstrate that matrine inhibits GBM cell growth through several components along the same pathway, which is illustrated in Figure 7.…”

Section: Discussionsupporting

confidence: 50%

“…On protein blots, we only observed significant changes in p27 in response to matrine. p27 is a regulator of cyclin‐dependent kinases (CDK); when bound, p27 inactivates CDKs and induces cell cycle arrest at G1, S, or G2 phases . Our data demonstrated that siRNA knockdown of p27 rescued GBM cells from matrine‐induced senescence and implicate p27 as a critical molecule mediating matrine‐induced cellular senescence.…”

Section: Discussionmentioning

confidence: 73%

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Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway

Zhou

Wang

et al. 2018

Cancer Medicine

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BackgroundMatrine, a traditional Chinese medicine, has recently been shown to have antitumor properties in diverse cancer cells. Here, we explored the effect of matrine on human glioblastoma multiforme (GBM) cells.MethodsGlioblastoma multiforme cell lines were treated with matrine to assess proliferation and viability using EdU and CCK8 assays. SA‐β‐gal assays were used to evaluate cellular senescence, and a cytokine array and ELISA assay were used to screen for secreted cytokines altered in GBM cells after matrine treatment. Immunohistochemistry and Western blot analysis were performed to evaluate protein levels in matrine‐treated cell lines and in samples obtained from orthotopic xenografts. Specific activators of AKT and IGF1 were used to identify the pathways mediating the effect.ResultsMatrine potently inhibited growth of GBM cell lines in vitro. Based on in situ assays, growth arrest induced by matrine was primarily achieved through induction of cellular senescence. Matrine treatment led to decreased expression of proteins involved in promoting cell growth, IGF1, PI3K, and pAKT. Exposure of cells to a small molecule activating AKT (SC79) and recombinant IGF1 led to a reduced number of senescent SA‐β‐gal‐positive cells in the presence of matrine. Finally, matrine inhibited growth of orthotopic xenografts established from luciferase‐stable‐U251 or luciferase‐stable‐P3 cells and prolonged overall survival in mice.ConclusionsThese results indicated that matrine arrested cell growth through inhibition of IGF1/PI3K/AKT signaling. Matrine warrants further investigation as a potential therapy in the treatment of patients with GBM.

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Section: Discussionsupporting

confidence: 50%

Section: Discussionmentioning

confidence: 73%

Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway

Zhou

Wang

et al. 2018

Cancer Medicine

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“…The sirtuins are members of a family of deacetylases (SIRT1 through SIRT7) that modulate numerous cellular processes [ 53 ]. SIRT1 and SIRT6 are nucleus-localized sirtuins that also modulate cellular senescence, and downregulation of SIRT1 and SIRT6 has been demonstrated to induce premature senescence in a variety of cell types [ 81 , 82 , 83 ]. In the present study, we determined that BLU9931 reduced SIRT1 and SIRT6 levels, leading to the induction of premature senescence in PDAC cells ( Figure 6 ).…”

Section: Discussionmentioning

confidence: 99%

FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer

Sasaki

Gomi

Yoshimura

et al. 2020

Cancers

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Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200).

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“…It was recently reported that sirtuin 6 (SIRT6), a protein presenting with HDAC-like senotherapeutic properties, inhibits NF-κB and EC senescence, suggesting AD therapeutic benefits (Lappas, 2012; Zhao et al, 2016).…”

Section: Senotherapeutics: Targeting Senescence In Alzheimer's Diseasementioning

confidence: 99%

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

Osorio

Kanukuntla

Diaz

et al. 2019

Front. Aging Neurosci.

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The amyloid hypothesis, the assumption that beta-amyloid toxicity is the primary cause of neuronal and synaptic loss, has been the mainstream research concept in Alzheimer's disease for the past two decades. Currently, this model is quietly being replaced by a more holistic, “systemic disease” paradigm which, like the aging process, affects multiple body tissues and organs, including the gut microbiota. It is well-established that inflammation is a hallmark of cellular senescence; however, the infection-senescence link has been less explored. Microbiota-induced senescence is a gradually emerging concept promoted by the discovery of pathogens and their products in Alzheimer's disease brains associated with senescent neurons, glia, and endothelial cells. Infectious agents have previously been associated with Alzheimer's disease, but the cause vs. effect issue could not be resolved. A recent study may have settled this debate as it shows that gingipain, a Porphyromonas gingivalis toxin, can be detected not only in Alzheimer's disease but also in the brains of older individuals deceased prior to developing the illness. In this review, we take the position that gut and other microbes from the body periphery reach the brain by triggering intestinal and blood-brain barrier senescence and disruption. We also surmise that novel Alzheimer's disease findings, including neuronal somatic mosaicism, iron dyshomeostasis, aggressive glial phenotypes, and loss of aerobic glycolysis, can be explained by the infection-senescence model. In addition, we discuss potential cellular senescence targets and therapeutic strategies, including iron chelators, inflammasome inhibitors, senolytic antibiotics, mitophagy inducers, and epigenetic metabolic reprograming.

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SIRT6 delays cellular senescence by promoting p27Kip1 ubiquitin-proteasome degradation

Cited by 27 publications

References 56 publications

Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway

Matrine induces senescence of human glioblastoma cells through suppression of the IGF1/PI3K/AKT/p27 signaling pathway

FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer

The Post-amyloid Era in Alzheimer's Disease: Trust Your Gut Feeling

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