Cellular senescence: a promising strategy for cancer therapy

( Seongju Lee ),( Jae-seon Lee ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.1

Cellular senescence, a permanent state of cell cycle arrest, is believed to have originally evolved to limit the proliferation of old or damaged cells. However, it has been recently shown that cellular senescence is a physiological and pathological program contributing to embryogenesis, immune response, and wound repair, as well as aging and age-related diseases. Unlike replicative senescence associated with telomere attrition, premature senescence rapidly occurs in response to various intrinsic and extrinsic insults. Thus, cellular senescence has also been considered suppressive mechanism of tumorigenesis. Current studies have revealed that therapy-induced senescence (TIS), a type of senescence caused by traditional cancer therapy, could play a critical role in cancer treatment. In this review, we outline the key features and the molecular pathways of cellular senescence. Better understanding of cellular senescence will provide insights into the development of powerful strategies to control cellular senescence for therapeutic benefit. Lastly, we discuss existing strategies for the induction of cancer cell senescence to improve efficacy of anticancer therapy. [BMB Reports 2019; 52(1): 35-41]

Gene regulatory cascade of senescence-associated NAC transcription factors activated by ETHYLENE-INSENSITIVE2-mediated leaf senescence signalling in <i>Arabidopsis</i>

Kim, Hyo Jung,Hong, Sung Hyun,Kim, You Wang,Lee, Il Hwan,Jun, Ji Hyung,Phee, Bong-Kwan,Rupak, Timilsina,Jeong, Hana,Lee, Yeonmi,Hong, Byoung Seok,Nam, Hong Gil,Woo, Hye Ryun,Lim, Pyung Ok Oxford University Press 2014 Journal of experimental botany Vol.65 No.14

<P>Leaf senescence is a finely tuned and genetically programmed degeneration process, which is critical to maximize plant fitness by remobilizing nutrients from senescing leaves to newly developing organs. Leaf senescence is a complex process that is driven by extensive reprogramming of global gene expression in a highly coordinated manner. Understanding how gene regulatory networks involved in controlling leaf senescence are organized and operated is essential to decipher the mechanisms of leaf senescence. It was previously reported that the trifurcate feed-forward pathway involving <I>EIN2</I>, <I>ORE1</I>, and <I>miR164</I> in <I>Arabidopsis</I> regulates age-dependent leaf senescence and cell death. Here, new components of this pathway have been identified, which enhances knowledge of the gene regulatory networks governing leaf senescence. Comparative gene expression analysis revealed six senescence-associated NAC transcription factors (TFs) (ANAC019, AtNAP, ANAC047, ANAC055, ORS1, and ORE1) as candidate downstream components of ETHYLENE-INSENSITIVE2 (EIN2). EIN3, a downstream signalling molecule of EIN2, directly bound the <I>ORE1</I> and <I>AtNAP</I> promoters and induced their transcription. This suggests that EIN3 positively regulates leaf senescence by activating <I>ORE1</I> and <I>AtNAP</I>, previously reported as key regulators of leaf senescence. Genetic and gene expression analyses in the <I>ore1 atnap</I> double mutant revealed that ORE1 and AtNAP act in distinct and overlapping signalling pathways. Transient transactivation assays further demonstrated that ORE1 and AtNAP could activate common as well as differential NAC TF targets. Collectively, the data provide insight into an EIN2-mediated senescence signalling pathway that coordinates global gene expression during leaf senescence via a gene regulatory network involving EIN3 and senescence-associated NAC TFs.</P>

Time-evolving genetic networks reveal a NAC troika that negatively regulates leaf senescence in <i>Arabidopsis</i>

Kim, Hyo Jung,Park, Ji-Hwan,Kim, Jingil,Kim, Jung Ju,Hong, Sunghyun,Kim, Jeongsik,Kim, Jin Hee,Woo, Hye Ryun,Hyeon, Changbong,Lim, Pyung Ok,Nam, Hong Gil,Hwang, Daehee National Academy of Sciences 2018 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.115 No.21

<▼1><P><B>Significance</B></P><P>Leaf senescence is regulated in a complex manner, involving time-dependent interactions with developmental and environmental signals. Genetic screens have identified key regulators of senescence, particularly late-stage senescence regulators. Recently, time-course gene-expression and network analyses, mostly analyses of static networks, have predicted many senescence regulators. However, senescence is defined by time-evolving networks, involving the temporal transition of interactions among senescence regulators. Here, we present time-evolving networks of NAM/ATAF/CUC (NAC) transcription factors, central regulators of leaf senescence in <I>Arabidopsis</I>, via time-course gene-expression analysis of NACs in their mutants. These time-evolving networks revealed a unique regulatory module of NACs that controls the timely induction of senescence-promoting processes at a presenescent stage of leaf aging.</P></▼1><▼2><P>Senescence is controlled by time-evolving networks that describe the temporal transition of interactions among senescence regulators. Here, we present time-evolving networks for NAM/ATAF/CUC (NAC) transcription factors in <I>Arabidopsis</I> during leaf aging. The most evident characteristic of these time-dependent networks was a shift from positive to negative regulation among NACs at a presenescent stage. ANAC017, ANAC082, and ANAC090, referred to as a “NAC troika,” govern the positive-to-negative regulatory shift. Knockout of the NAC troika accelerated senescence and the induction of other <I>NAC</I>s, whereas overexpression of the NAC troika had the opposite effects. Transcriptome and molecular analyses revealed shared suppression of senescence-promoting processes by the NAC troika, including salicylic acid (SA) and reactive oxygen species (ROS) responses, but with predominant regulation of SA and ROS responses by ANAC090 and ANAC017, respectively. Our time-evolving networks provide a unique regulatory module of presenescent repressors that direct the timely induction of senescence-promoting processes at the presenescent stage of leaf aging.</P></▼2>

Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot

Kwon, Yoojin,Kim, Ji Wook,Jeoung, Jo Ae,Kim, Mi-Sung,Kang, Chanhee Korean Society for Molecular and Cellular Biology 2017 Molecules and cells Vol.40 No.9

When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.

Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot

권유진,김지욱,정조애,김미성,강찬희 한국분자세포생물학회 2017 Molecules and cells Vol.40 No.9

When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the devel-opment of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.

HPF1 regulates tendon stem/progenitor cell senescence and tendon repair via PARP1-mediated poly-ADP ribosylation of HuR

Han Weifeng,GU Dongqiang,Chen Hongguang,Tao Xu,Chen Lei 한국유전학회 2024 Genes & Genomics Vol.46 No.1

Background Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis. However, the specific mechanism of TSPCs aging is still unclear. Objective This study aims to explore the role and molecular mechanism of HPF1 in the aging of TSPCs. Methods Young and aged TSPCs (Y-TSPCs and A-TSPCs) were acquired from 3 to 4 and 24–26-month-old Sprague–Dawley male rats, TSPCs (Y-TSPCs and A-TSPCs) were subjected to senescence-associated β-galactosidase (SA-β-Gal))staining and telomerase activity detection, p16, p21, Scx, Tnmd, Col1, Col3HPF1 and PAPR1 expression levels were detected by Western blot or Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR), Reciprocal co-immunoprecipitation (co-IP) was used to explore the interaction between HPF1 and PARP1. Ribonucleoprotein immunoprecipitation (RNP-IP) was used to analyze the binding of HuR to the senescence marker gene mRNAs, IP was used to perform HPF1 to the PARylation of HuR, and the half-life of p16 and p21 were detected. Finally, we established an in vivo model, and the tendon tissue was used to perform hematoxylin and eosin (HE) and masson’s trichrome staining, as well as the immunohistochemical analysis of Col I and TNMD. Results Compared with Y-TSPCs, A-TSPCs had significantly enhanced cell senescence and significantly reduced tendon differentiation ability, and significantly increased the expression of HPF1 and PARP1. In addition, HPF1 and PARP1 interacted and coordinated the senescence and differentiation of TSPCs, HPF1 could also regulate the expression of p21 and p21, the interaction of p16 or p21 with HuR, and the poly-ADP ribosylation of PARP1 to HuR. HPF1 overexpression and siHuR co-transfection significantly reduced the half-life of p16 and p21, and HPF1 and PARP1 regulated the mRNA levels of p16 and p21 through HuR. Finally, in vivo experiments have shown that HPF1 or PARP1 overexpression could both inhibit the ability of tendon differentiation and promote cell senescence. Conclusions HPF1 promoted the senescence of TSPCs and inhibits the tendon differentiation of TSPCs through PARP1-mediated poly-ADP ribosylation of HuR. Similar content being viewed by others Background Tendon stem/progenitor cells (TSPCs) play a vital role in tendon repair, regeneration and homeostasis. However, the specific mechanism of TSPCs aging is still unclear. Objective This study aims to explore the role and molecular mechanism of HPF1 in the aging of TSPCs. Methods Young and aged TSPCs (Y-TSPCs and A-TSPCs) were acquired from 3 to 4 and 24–26-month-old Sprague–Dawley male rats, TSPCs (Y-TSPCs and A-TSPCs) were subjected to senescence-associated β-galactosidase (SA-β-Gal))staining and telomerase activity detection, p16, p21, Scx, Tnmd, Col1, Col3HPF1 and PAPR1 expression levels were detected by Western blot or Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR), Reciprocal co-immunoprecipitation (co-IP) was used to explore the interaction between HPF1 and PARP1. Ribonucleoprotein immunoprecipitation (RNP-IP) was used to analyze the binding of HuR to the senescence marker gene mRNAs, IP was used to perform HPF1 to the PARylation of HuR, and the half-life of p16 and p21 were detected. Finally, we established an in vivo model, and the tendon tissue was used to perform hematoxylin and eosin (HE) and masson’s trichrome staining, as well as the immunohistochemical analysis of Col I and TNMD. Results Compared with Y-TSPCs, A-TSPCs had significantly enhanced cell senescence and significantly reduced tendon differentiation ability, and significantly increased the expression of HPF1 and PARP1. In addition, HPF1 and PARP1 interacted and coordinated the senescence and differentiation of TSPCs, HPF1 could also regulate the expression of p21 and p21, the interaction of p16 or p21 with HuR, and the poly-ADP ribosylation of PARP1 to HuR. HPF1 overexpression and siHuR co-transfection significantly reduced the half-life of p16 and p21, and HPF1 and PARP1 regulated the mRNA levels of p16 and p21 through HuR. Finally, in vivo experiments have shown that HPF1 or PARP1 overexpression could both inhibit the ability of tendon differentiation and promote cell senescence. Conclusions HPF1 promoted the senescence of TSPCs and inhibits the tendon differentiation of TSPCs through PARP1-mediated poly-ADP ribosylation of HuR. Similar content being viewed by others

Inhibition of miR-146a-5p and miR-8114 in Insulin-Secreting Cells Contributes to the Protection of Melatonin against Stearic Acid-Induced Cellular Senescence by Targeting Mafa

Shenghan Su,Qingrui Zhao,Lingfeng Dan,Yuqing Lin,Xuebei Li,Yunjin Zhang,Chunxiao Yang,Yimeng Dong,Xiaohan Li,Romano Regazzi,Changhao Sun,Xia Chu,Huimin Lu 대한내분비학회 2022 Endocrinology and metabolism Vol.37 No.6

Background: Chronic exposure to elevated levels of saturated fatty acids results in pancreatic β-cell senescence. However, targets and effective agents for preventing stearic acid-induced β-cell senescence are still lacking. Although melatonin administration can protect β-cells against lipotoxicity through anti-senescence processes, the precise underlying mechanisms still need to be explored. Therefore, we investigated the anti-senescence effect of melatonin on stearic acid-treated mouse β-cells and elucidated the possible role of microRNAs in this process. Methods: β-Cell senescence was identified by measuring the expression of senescence-related genes and senescence-associated β-galactosidase staining. Gain- and loss-of-function approaches were used to investigate the involvement of microRNAs in stearic acid-evoked β-cell senescence and dysfunction. Bioinformatics analyses and luciferase reporter activity assays were applied to predict the direct targets of microRNAs. Results: Long-term exposure to a high concentration of stearic acid-induced senescence and upregulated miR-146a-5p and miR-8114 expression in both mouse islets and β-TC6 cell lines. Melatonin effectively suppressed this process and reduced the levels of these two miRNAs. A remarkable reversibility of stearic acid-induced β-cell senescence and dysfunction was observed after silencing miR-146a-5p and miR-8114. Moreover, V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa) was verified as a direct target of miR-146a-5p and miR-8114. Melatonin also significantly ameliorated senescence and dysfunction in miR-146a-5pand miR-8114-transfected β-cells. Conclusion: These data demonstrate that melatonin protects against stearic acid-induced β-cell senescence by inhibiting miR-146a-5p and miR-8114 and upregulating Mafa expression. This not only provides novel targets for preventing stearic acid-induced β-cell dysfunction, but also points to melatonin as a promising drug to combat type 2 diabetes progression.

Fatty acid oxidation regulates cellular senescence by modulating the autophagy-SIRT1 axis

( Seungyeon Yang ),( Subin Moon ),( Soojung Claire Hur ),( Seung Min Jeong ) 생화학분자생물학회 2023 BMB Reports Vol.56 No.12

Senescence, a cellular process through which damaged or dysfunctional cells suppress the cell cycle, contributes to aging or age-related functional decline. Cell metabolism has been closely correlated with aging processes, and it has been widely recognized that metabolic changes underlie the cellular alterations that occur with aging. Here, we report that fatty acid oxidation (FAO) serves as a critical regulator of cellular senescence and uncover the underlying mechanism by which FAO inhibition induces senescence. Pharmacological or genetic ablation of FAO results in a p53-dependent induction of cellular senescence in human fibroblasts, whereas enhancing FAO suppresses replicative senescence. We found that FAO inhibition promotes cellular senescence through acetyl-CoA, independent of energy depletion. Mechanistically, increased formation of autophagosomes following FAO inhibition leads to a reduction in SIRT1 protein levels, thereby contributing to senescence induction. Finally, we found that inhibition of autophagy or enforced expression of SIRT1 can rescue the induction of senescence as a result of FAO inhibition. Collectively, our study reveals a distinctive role for the FAO-autophagy-SIRT1 axis in the regulation of cellular senescence. [BMB Reports 2023; 56(12): 651-656]

오이(Cucumis sativus L.) 떡잎의 노쇠화 관련 유전자의 발현 및 수분 스트레스의 영향

이주연 ( Ju Yeon Lee ),김대재 ( Dae Jae Kim ) 충북대학교 과학교육연구소 2011 과학교육연구논총 Vol.26 No.2

Plant senescence is final stage of development and lead to their death an organ and an organism. Senescence in plant or plant organism is regulated by genetic program. Several genes are identified senescence-associated genes in cucumber. This study is Whether each genes have experiment effect between their gene expression and senescence that natural or according to water-stress. Used genes were sen 9-6 (glycosyltransferase), sen 137 (acyl-CoA thioesterase), sen 211 (DNA photolyase), sen 275 (unnamed protein product) and sen 355 (3-oxo-5-alpha-steroid 4-dehydrogenase family protein). Function of genes was identified through NCBI-GenBank database investigation using tblastx and blastx searching module. This study were used cucumber cotyledons that detached on the 14th, 21th, 28th day after seeds sowing and senescence stage Ⅰ(50% yellow), stege Ⅱ(70% yellow), stege Ⅲ(>90% yellow) until 50 days of cucumber development. We prepared cDNAs from mRNA using reverse transcription (RT) and performed PCR using gene specific primers. The sen 9-6, sen 137 and sen 355 genes were up-regulated in senescence stage, sen 211 showed slightly increased expression until 28th day and decreasing in senescence stage. There is no change in sen 275 gene expression pattern. Therefore, sen 9-6, sen 137 and sen 335 would be senescence-associated genes. We also examined for water-stress effect of these senescence-associated genes. The sen 137, sen 211 and sen 355 showed similar expression patterns between water-stressed and control sample. The sen 9-6 and sen 275 showed some response to water-stress in gene expression which is up-regulation in gene expression.

오이(Cucumis sativus L.) 떡잎의 노쇠화와 수분 스트레스 관련 유전자들의 발현 연구

최선림 ( Seon Lim Choi ),김대재 ( Dae Jae Kim ) 충북대학교 과학교육연구소 2011 과학교육연구논총 Vol.26 No.2

Plant senescence is important process for plant development, and is genetically regulated in the last stage of organ development. Senescence is one type of programmed cell death(PCD) that occurs in plants. Previously, several senescence-associated genes(SAGs) of cucumber(Cucumis sativus L.) were selected to study the gene expression patterns and to characterize the water-stress response which may affect in those genes expression. The genes are Sen 36(FHA domain proteins encoding gene), Sen 49(『-carotenoid and 』-carotenoid synthesis related), Sen 54(metallothionine encoding gene), Sen 80(unknown gene), Sen 124(DEAD Box RNA Helicase encoding gene) and Sen 140(HUA Enhancer 2 encoding gene). First, natural senescence was examined from the days at 14th, 21th, 28th and senescence stage Ⅰ(50% yellow; SI), senescence stage Ⅱ(70% yellow; SⅡ) and senescence stage Ⅲ(>90% yellow; SⅢ) according to chlorophyll contents in cucumber cotyledons. Secondly, water-stress was applied to the cotyledons at day 14 after seed sowing. The cotyledons were used for total RNA purification and then cDNAs were synthesized. The genes expression level was examined by PCR experiment. In natural senescence, Sen 36 showed strong gene expression at the stage of senescence development in cucumber cotyledon. Sen 49 and Sen 54 were consistently expressed in all developmental stages. Sen 80 gene showed some fluctuation in gene expression, but the gene is active throughout development. Sen 124 and Sen 140 genes were expressed in all stages of development. In water stress experiment, Sen 36 gene showed inconsistent expression. And rest of the genes(Sen49, Sen54, Sen80, Sen124 and Sen140) were similar to that of the natural senescence results which expressed consistently.