Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

Delfarah, Alireza; Parrish, Sydney; Junge, Jason A.; Jm, Yang; Seo, Frances; Li, Si; Mac, John; Wang, Pin; Fraser, Scott E.; Graham, Nicholas A.

doi:10.1074/jbc.ra118.005806

Cited by 40 publications

(52 citation statements)

References 60 publications

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“…More recently, metabolomic approaches on extracellular metabolites released by senescent fibroblasts confirmed a shift toward glycolysis compared to young cells (James et al, 2015). This general mechanism, however, is more or less pronounced depending on the cell type and shows some exceptions, such as senescent human mammary epithelial cells where glucose consumption and lactate secretion do not increase (Delfarah et al, 2019).…”

Section: Metabolic Reprogramming In Cellular Senescencementioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD +-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

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Section: Metabolic Reprogramming In Cellular Senescencementioning

confidence: 99%

Where Metabolism Meets Senescence: Focus on Endothelial Cells

et al. 2019

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“…In particular, replicative senescence in primary human mammary epithelial cells is accompanied by a marked inhibition of nucleotide synthesis without any alteration in glycolysis. These findings demonstrate that inhibition of nucleotide synthesis plays a causative role in the establishment of replicative senescence [171].…”

Section: Energy Metabolism and Cellular Senescencementioning

confidence: 63%

The Emerging Role of Senescence in Ocular Disease

Sreekumar

Hinton

Kannan

2020

Oxidative Medicine and Cellular Longevity

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Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far and the present review describes the recent research on this topic. We present an overview of the types of senescence, pathways of senescence, senescence-associated secretory phenotype (SASP), the role of mitochondria, and their functional implications along with antisenescent therapies. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the SASP. An updated summary of a number of new members of the ever-growing SASP family is presented. Further, we introduce the significance of mechanisms by which mitochondria may participate in the development of cellular senescence. Emerging evidence shows that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Based on recent studies, there is reasonable evidence that senescence could be a modifiable factor, and hence, it may be possible to delay age-related diseases by modulating basic aging mechanisms using SASP inhibitors/senolytic drugs. Thus, antisenescent therapies in aging and age-related diseases appear to have a promising potential.

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“…We have previously found that HMECs enter senescence at ~40 population doublings (PD) ( Fig. 1A) and exhibit molecular markers of senescence including upregulation of senescence-associated β-galactosidase (SA-β-gal), upregulation of the cell cycle inhibitor p21, and cessation of DNA synthesis (Delfarah et al 2019).…”

Section: Replicative Senescence Alters the Hmec Proteomementioning

confidence: 99%

“…We have previously shown that expression of human telomerase reverse transcriptase (hTERT) immortalizes HMECs and enables bypass of replicative senescence (Delfarah et al 2019). We thus used LC-MS proteomics to compare hTERT-immortalized HMECs to senescent HMECs expressing the negative control protein luciferase.…”

Section: The Proteome Of Htert-immortalized Hmecs Resembles That Of Pmentioning

confidence: 99%

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

Delfarah

Zheng

et al. 2020

Preprint

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Cellular senescence is the natural program by which cells enter a permanent cell cycle arrest in response to stresses including replicative exhaustion, oncogenic signaling, or DNA damage. Although senescence exerts beneficial effects by acting as a barrier against tumorigenesis, senescent cells can also drive chronic inflammation and age-related diseases through secretion of cytokines and other inflammatory proteins. Therefore, the identification of senolytic compounds that specifically eliminate senescent cells has become an area of great therapeutic promise. Here, we used mass spectrometry-based proteomics to identify senescence biomarkers in primary human mammary epithelial cells (HMECs), a model system for aging. By integrating proteomic data from replicative senescence, immortalization by telomerase reactivation, and drug-induced senescence, we identified a robust HMEC proteomic signature of senescence consisting of 57 upregulated and 29 downregulated proteins. This senescence signature identified both well-known senescence biomarkers, including downregulation of the nuclear lamina protein lamin-B1 (LMNB1), as well as novel biomarkers such as upregulation of the β-galactoside-binding protein galectin-7 (LGALS7). Then, we integrated our proteomic signature of senescence with large-scale drug screening databases to predict that EGFR inhibitors, MEK inhibitors, and dasatinib are novel senolytics in HMEC. Taken together, our results support that the combination of quantitative proteomics and public drug screening databases is a powerful approach to identify senescence biomarkers and novel senolytic compounds.

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Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

Cited by 40 publications

References 60 publications

Where Metabolism Meets Senescence: Focus on Endothelial Cells

Where Metabolism Meets Senescence: Focus on Endothelial Cells

The Emerging Role of Senescence in Ocular Disease

Identification of a Proteomic Signature of Senescence in Primary Human Mammary Epithelial Cells

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