SUV39H2/KMT1B Inhibits the cardiomyocyte senescence phenotype by down-regulating BTG2/PC3

Objective: To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. Methods: An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a CCK-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Results: Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Conclusion: Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.

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Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents

Cells ◽

10.3390/cells8121501 ◽

2019 ◽

Vol 8 (12) ◽

pp. 1501 ◽

Cited By ~ 14

Author(s):

Agnieszka Bojko ◽

Joanna Czarnecka-Herok ◽

Agata Charzynska ◽

Michal Dabrowski ◽

Ewa Sikora

Keyword(s):

Dna Damage ◽

Comparative Analysis ◽

Cancer Cells ◽

Chemotherapeutic Agents ◽

Double Stranded Dna ◽

Secretory Phenotype ◽

Paclitaxel Treatment ◽

Senescence Phenotype ◽

Mcf 7 ◽

Intermediate Effect

It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.

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The Inhibitor of Cyclin-Dependent Kinase4a (INK4a) Signaling Pathway Induces Aging in Human Skeletal Muscle Myoblasts and Decreases the Mitochondrial Membrane Potential

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2019.2127 ◽

2019 ◽

Vol 9 (9) ◽

pp. 1192-1198

Author(s):

Dong Yan ◽

Xiang Liao ◽

Li-Xia Zhao ◽

Chang-Hong Xiao

Keyword(s):

Skeletal Muscle ◽

Flow Cytometry ◽

Membrane Potential ◽

Signaling Pathway ◽

Mitochondrial Membrane Potential ◽

Mitochondrial Membrane ◽

Human Skeletal Muscle ◽

Lentiviral Vector ◽

Accelerated Aging ◽

Senescence Phenotype

The effect of the inhibitor of cyclin-dependent kinase4a (INK4a) signaling pathway on myoblastic aging was studied in this paper. Human skeletal muscle myoblasts were transfected with a recombinant lentiviral vector, pLVX-p16INK4a, encoding the p16INK4a gene, and RT-qPCR and western blotting were used to identify p16INK4a gene transcription and protein expression. The degree of cell senescence was assessed using Senescence-associated β-galactosidase staining. flow cytometry and JC-1 staining was used to analyze the mitochondrial membrane potential (MMP). The senescence phenotype was observed in myoblasts transfected with p16INK4a, the MMP was significantly decrease in p16INK4a-transfected myoblasts, while the MMP was decreased only slightly in control cells. Upregulation of the INK4a signaling pathway directly induced aging in human skeletal muscle myoblasts. Moreover, INK4a signaling pathway activated the mitochondrial pro-aging pathway by reducing the MMP, which indirectly accelerated aging in myoblasts.

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Cytotoxicity of chemotherapeutic agents in glyceraldehyde-3-phosphate dehydrogenase-depleted human lung carcinoma A549 cells with the accelerated senescence phenotype

Anti-Cancer Drugs ◽

10.1097/cad.0b013e32835e3378 ◽

2013 ◽

Vol 24 (4) ◽

pp. 366-374 ◽

Cited By ~ 6

Author(s):

Manali Phadke ◽

Natalia Krynetskaia ◽

Evgeny Krynetskiy

Keyword(s):

Lung Carcinoma ◽

Human Lung ◽

A549 Cells ◽

Chemotherapeutic Agents ◽

Human Lung Carcinoma ◽

Accelerated Senescence ◽

Senescence Phenotype

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The murine dialysis fistula model exhibits a senescence phenotype: pathobiological mechanisms and therapeutic potential

AJP Renal Physiology ◽

10.1152/ajprenal.00308.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. F1493-F1499 ◽

Cited By ~ 10

Author(s):

Karl A. Nath ◽

Daniel R. O’Brien ◽

Anthony J. Croatt ◽

Joseph P. Grande ◽

Allan W. Ackerman ◽

...

Keyword(s):

Therapeutic Potential ◽

Premature Senescence ◽

Sequencing Analysis ◽

Proof Of Concept ◽

Vascular Responses ◽

Dialysis Fistula ◽

Clinical Interest ◽

Novel Concept ◽

Senescence Phenotype ◽

Telomere Erosion

There is no therapy that promotes maturation and functionality of a dialysis arteriovenous fistula (AVF). The search for such therapies largely relies on evaluation of vascular responses and putative therapies in experimental AVFs. We studied an AVF in mice with chronic kidney disease (CKD). We demonstrate numerous stressors in the vein of the AVF-CKD group, including pathological shear, mitogenic, inflammatory, and hypoxia-reoxygenation stress. Because stress promotes premature senescence, we examined whether senescence is induced in the vein of the AVF-CKD model. We demonstrate a senescence phenotype in the AVF-CKD model, as indicated by increased expression of p16Ink4a, p21Cip1, and p53 and expected changes for certain senescence-associated microRNAs. RNA-sequencing analysis demonstrated differential expression of ~10,000 genes, including upregulation of proinflammatory and proliferative genes, in the vein of the AVF-CKD group. The vein in the AVF-CKD group exhibited telomere erosion and increased senescence-associated β-galactosidase activity and staining. Senescence was induced in the artery of the AVF-CKD group and in the vein of the AVF without CKD. Finally, given the rapidly rising clinical interest in senolytics, we provide proof of concept of senolytics as a therapeutic approach by demonstrating that senolytics decrease p16Ink4a expression in the AVF-CKD model. This study introduces a novel concept underlying the basis for maturational and functional failure in human dialysis AVFs and identifies a new target for senolytic therapy.

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MELK-T1, a small-molecule inhibitor of protein kinase MELK, decreases DNA-damage tolerance in proliferating cancer cells

Bioscience Reports ◽

10.1042/bsr20150194 ◽

2015 ◽

Vol 35 (6) ◽

Cited By ~ 39

Author(s):

Lijs Beke ◽

Cenk Kig ◽

Joannes T. M. Linders ◽

Shannah Boens ◽

An Boeckx ◽

...

Keyword(s):

Dna Damage ◽

Protein Kinase ◽

Cancer Cells ◽

Small Molecule ◽

Damage Tolerance ◽

Replication Stress ◽

Small Molecule Inhibitor ◽

Dna Damage Tolerance ◽

Molecule Inhibitor ◽

Senescence Phenotype

Protein kinase MELK has oncogenic properties and is highly overexpressed in some tumors. In the present study, we show that a novel MELK inhibitor causes both the inhibition and degradation of MELK, culminating in replication stress and a senescence phenotype.

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