Molecular Basis for the Cellular Senescence Program and Its Application to Anticancer Therapy

2006 ◽  
Vol 70 (5) ◽  
pp. 1076-1081 ◽  
Author(s):  
Yoshinori KATAKURA
Keyword(s):  
Cellular Senescence ◽  
Molecular Basis ◽  
Anticancer Therapy ◽  
Senescence Program

scholarly journals Restoration of the Cellular Senescence Program and Repression of Telomerase by Human Chromosome 3

1995 ◽  
Vol 86 (10) ◽  
pp. 899-904 ◽  
Author(s):  
Hiroshi Ohmura ◽  
Hidetoshi Tahara ◽  
Mikio Suzuki ◽  
Toshinori Ide ◽  
Motoyuki Shimizu ◽  
...  
Keyword(s):  
Human Chromosome ◽  
Cellular Senescence ◽  
Chromosome 3 ◽  
Human Chromosome 3 ◽  
Senescence Program

Targeting cancer's Achilles’ heel: role of BCL-2 inhibitors in cellular senescence and apoptosis

2019 ◽  
Vol 11 (17) ◽  
pp. 2287-2312 ◽  
Author(s):  
Aarti Anantram ◽  
Mariam Degani
Keyword(s):  
Nuclear Magnetic Resonance ◽  
Magnetic Resonance ◽  
Tumor Growth ◽  
Cellular Senescence ◽  
Anticancer Agents ◽  
Anticancer Therapy ◽  
Targeted Chemotherapy ◽  
Structure Based Drug Design ◽  
Selective Targeting

Members of the antiapoptotic BCL-2 proteins are involved in tumor growth, progression and survival, and are also responsible for chemoresistance to conventional anticancer agents. Early efforts to target these proteins yielded some active compounds; however, newer methodologies involving structure-based drug design, Nuclear Magnetic Resonance (NMR)-based screening and fragment-based screening yielded more potent compounds. Discovery of specific as well as nonspecific inhibitors of this class of proteins has resulted in great advances in targeted chemotherapy and decrease in chemoresistance. Here, we review the history and current progress in direct as well as selective targeting of the BCL-2 proteins for anticancer therapy.

scholarly journals A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts

2011 ◽  
Vol 19 (4) ◽  
pp. 713-721 ◽  
Author(s):  
R Faraonio ◽  
P Salerno ◽  
F Passaro ◽  
C Sedia ◽  
A Iaccio ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Senescence Program

scholarly journals Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3402
Author(s):  
Chieh-Yu Shen ◽  
Cheng-Hsun Lu ◽  
Cheng-Han Wu ◽  
Ko-Jen Li ◽  
Yu-Min Kuo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Systemic Sclerosis ◽  
Cellular Senescence ◽  
Cancer Incidence ◽  
Molecular Basis ◽  
Chromosome Instability ◽  
Vascular Endothelial Cell ◽  
Accelerated Aging ◽  
Immune Dysfunction ◽  
Tissue Fibrosis

Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.

Abstract 2247: Histone H3 cleavage via Cathepsin L drives a cellular senescence program

2014 ◽  
Author(s):  
Luis F. Duarte ◽  
Andrew R. Young ◽  
Hsan-Au Wu ◽  
Taniya Panda ◽  
Zichen Wang ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Cathepsin L ◽  
Histone H3 ◽  
Senescence Program

scholarly journals The Interaction of Viruses with the Cellular Senescence Response

Biology ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 455
Author(s):  
Rocío Seoane ◽  
Santiago Vidal ◽  
Yanis Hichem Bouzaher ◽  
Ahmed El Motiam ◽  
Carmen Rivas
Keyword(s):  
Virus Replication ◽  
Cellular Senescence ◽  
Therapeutic Strategy ◽  
Viral Infections ◽  
Viral Propagation ◽  
Age Related ◽  
Control Virus ◽  
Potential Impact ◽  
Senescence Program ◽  
The Relationship

Cellular senescence is viewed as a mechanism to prevent malignant transformation, but when it is chronic, as occurs in age-related diseases, it may have adverse effects on cancer. Therefore, targeting senescent cells is a novel therapeutic strategy against senescence-associated diseases. In addition to its role in cancer protection, cellular senescence is also considered a mechanism to control virus replication. Both interferon treatment and some viral infections can trigger cellular senescence as a way to restrict virus replication. However, activation of the cellular senescence program is linked to the alteration of different pathways, which can be exploited by some viruses to improve their replication. It is, therefore, important to understand the potential impact of senolytic agents on viral propagation. Here we focus on the relationship between virus and cellular senescence and the reported effects of senolytic compounds on virus replication.

scholarly journals Cytoplasmic innate immune sensing by the caspase-4 non-canonical inflammasome promotes cellular senescence

2020 ◽  
Author(s):  
Irene Fernández-Duran ◽  
Núria Tarrats ◽  
Jodie Birch ◽  
Priya Hari ◽  
Fraser R. Millar ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Stress Responses ◽  
Tumour Suppressor ◽  
Human Diploid Fibroblasts ◽  
Cycle Arrest ◽  
Tumour Suppressor Protein ◽  
Immune Sensing ◽  
Senescence Program ◽  
Innate Immune Sensing

SummaryCytoplasmic recognition of microbially derived lipopolysaccharides (LPS) in human cells is elicited by the inflammatory cysteine aspartic proteases caspase-4 and caspase-5, which activate non-canonical inflammasomes inducing a form of inflammatory programmed cell death termed pyroptosis. Here we show that LPS mediated activation of the non-canonical inflammasome also induces cellular senescence and the activation of tumour suppressor stress responses in human diploid fibroblasts. Interestingly, this LPS-induced senescence is dependent on caspase-4, the pyroptotic effector protein gasdermin-D and the tumour suppressor protein p53. Also, experiments with a catalytically deficient mutant suggest that caspase-4 proteolytic activity is not necessary for its role in senescence. Furthermore, we found that the caspase-4 non-canonical inflammasome is induced and assembled during Ras-mediated oncogene-induced senescence (OIS). Moreover, targeting caspase-4 in OIS showed that the non-canonical inflammasome is critical for SASP activation and contributes to reinforcing the cell cycle arrest in OIS. Finally, we observed that caspase-4 induction occurs in vivo in models of tumour suppression and ageing. Altogether, we are unveiling that cellular senescence is induced by cytoplasmic microbial LPS recognition by the caspase-4 non-canonical inflammasome and that this pathway is conserved in the senescence program induced by oncogenic stress.

scholarly journals Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability To Stabilize p53

2001 ◽  
Vol 21 (5) ◽  
pp. 1552-1564 ◽  
Author(s):  
Andrei Seluanov ◽  
Vera Gorbunova ◽  
Ayellet Falcovitz ◽  
Alex Sigal ◽  
Michael Milyavsky ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Cellular Response ◽  
Human Fibroblasts ◽  
Proteasome Inhibitors ◽  
Anticancer Therapy ◽  
Cellular Function ◽  
Normal Aging ◽  
Exogenous Expression

ABSTRACT The cellular function of p53 is complex. It is well known that p53 plays a key role in cellular response to DNA damage. Moreover, p53 was implicated in cellular senescence, and it was demonstrated that p53 undergoes modification in senescent cells. However, it is not known how these modifications affect the ability of senescent cells to respond to DNA damage. To address this question, we studied the responses of cultured young and old normal diploid human fibroblasts to a variety of genotoxic stresses. Young fibroblasts were able to undergo p53-dependent and p53-independent apoptosis. In contrast, senescent fibroblasts were unable to undergo p53-dependent apoptosis, whereas p53-independent apoptosis was only slightly reduced. Interestingly, instead of undergoing p53-dependent apoptosis, senescent fibroblasts underwent necrosis. Furthermore, we found that old cells were unable to stabilize p53 in response to DNA damage. Exogenous expression or stabilization of p53 with proteasome inhibitors in old fibroblasts restored their ability to undergo apoptosis. Our results suggest that stabilization of p53 in response to DNA damage is impaired in old fibroblasts, resulting in induction of necrosis. The role of this phenomenon in normal aging and anticancer therapy is discussed.

scholarly journals miR-22 represses cancer progression by inducing cellular senescence

2011 ◽  
Vol 193 (2) ◽  
pp. 409-424 ◽  
Author(s):  
Dan Xu ◽  
Fumitaka Takeshita ◽  
Yumiko Hino ◽  
Saori Fukunaga ◽  
Yasusei Kudo ◽  
...  
Keyword(s):  
Breast Carcinoma ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cellular Senescence ◽  
Cell Invasion ◽  
Senescent Phenotype ◽  
Tumor Growth And Metastasis ◽  
Senescence Program

Cellular senescence acts as a barrier to cancer progression, and microRNAs (miRNAs) are thought to be potential senescence regulators. However, whether senescence-associated miRNAs (SA-miRNAs) contribute to tumor suppression remains unknown. Here, we report that miR-22, a novel SA-miRNA, has an impact on tumorigenesis. miR-22 is up-regulated in human senescent fibroblasts and epithelial cells but down-regulated in various cancer cell lines. miR-22 overexpression induces growth suppression and acquisition of a senescent phenotype in human normal and cancer cells. miR-22 knockdown in presenescent fibroblasts decreased cell size, and cells became more compact. miR-22–induced senescence also decreases cell motility and inhibits cell invasion in vitro. Synthetic miR-22 delivery suppresses tumor growth and metastasis in vivo by inducing cellular senescence in a mouse model of breast carcinoma. We confirmed that CDK6, SIRT1, and Sp1, genes involved in the senescence program, are direct targets of miR-22. Our study provides the first evidence that miR-22 restores the cellular senescence program in cancer cells and acts as a tumor suppressor.

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