Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation

Marmisolle, Inés; Martínez, Jennyfer; Liu, Jie; Mastrogiovanni, Mauricio; Fergusson, Marı́a M.; Rovira, Ilsa I.; Castro, Laura; Trostchansky, Andrés; Moreno, Marı́a; Cao, Liu; Finkel, Toren; Quijano, Celia

doi:10.1016/j.abb.2016.10.016

Cited by 22 publications

(14 citation statements)

References 51 publications

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“…This study unveils a role for FASN in controlling senescence establishment that contributes to explain the effect of FASN inhibitor, C75 27 . Importantly, C75 was reported to inhibit senescence in human diploid fibroblasts 21 , although it was unclear which senescent pathway was affected, whereas other reports show that C75 induce senescence in fibroblast 48 . Here we report that cellular senescence is inhibited in HSCs not only by treatment with C75 but also by FASN knockdown using a specific shRNA.…”

Section: Discussionmentioning

confidence: 98%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulation.

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Section: Discussionmentioning

confidence: 98%

FASN activity is important for the initial stages of the induction of senescence

et al. 2019

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“…10 Mavrogonatou et al 34 reported that there was a link between p38 MAPK pathway and oxidative stress, and both of them were involved in TNF-a-induced premature senescence of human dermal fibroblasts. Both oxidative stress and p38 MAPK pathway participated in metabolic perturbation-triggered senescence of human primary fibroblasts 35 and TNF-a-induced premature senescence of human dermal fibroblasts. 34 Suppression of p38 MAPK pathway could block the accumulation of ROS in senescent skin fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

Xiang

Zhan

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Conjunctivochalasis (CCH) is a common ocular disease and has received extensive attention recently. However, its exact pathogenesis remains largely unknown. Owing to the high morbidity of CCH in older people, this study aimed to investigate whether cellular senescence contributes to CCH progression and the underlying mechanism. METHODS. Loose conjunctival tissues from CCH patients (n ¼ 13) and normal conjunctival tissues from age-matched persons (n ¼ 12) were obtained and the fibroblasts were separately induced and obtained. Cellular senescence, and the expression of senescence-associated genes (p53 and p21) and p38 in CCH conjunctival tissues and normal controls, were determined by senescence-associated b-galactosidase (SA-b-Gal) staining and quantitative (q)RT-PCR, respectively. To explore the effects of p38 on cellular senescence in CCH fibroblasts, small interfering RNA (siRNA) targeting p38 (siP38) and p38-specific inhibitor SB203580 was performed in CCH fibroblasts. Then, cellular senescence, cell viability, reactive oxygen species (ROS) production, and gene expression were detected according to the corresponding methods. RESULTS. CCH conjunctival tissues had significantly more senescent cells, evidenced by more SA-b-Gal-positive cells, and higher expression of senescence-associated genes (p53 and p21) and p38. CCH fibroblasts transfected with siP38 or treated with SB203580 had obviously reduced numbers of senescent cells, decreased ROS production, and increased cell viability, as well as reduced expression of senescence-associated genes. Meanwhile, blocking p38 signaling decreased the expression of p53 and p21. CONCLUSIONS. Therefore, these findings indicate that cellular senescence might be a causative factor for CCH. P38 signaling might play an important role in the progress of cellular senescence in CCH fibroblasts via manipulation of p53/p21 signaling.

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“…Of note, in addition to the activation of the DNA damage-response cascade of molecular events, DOX produces a prompt reduction in the levels of acetyl-CoA carboxylase 1, the enzyme that catalyzes the rate-limiting step in fatty acid synthesis. Such induction of synchronized inhibition of proliferation and anabolism by DOX was seen in pulmonary fibroblasts [ 94 ]. In a recent study, cardiac fibroblasts exposed to DOX prematurely acquired a senescent phenotype, too, as shown by the increases in SA- β -gal activity and the expression of senescence markers p16 INK4a and p21 [ 95 ].…”

Section: Cardiac Fibroblastsmentioning

confidence: 99%

Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity

Cappetta

Angelis

Sapio

et al. 2017

Oxidative Medicine and Cellular Longevity

291

214

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The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.

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Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation

Cited by 22 publications

References 51 publications

FASN activity is important for the initial stages of the induction of senescence

FASN activity is important for the initial stages of the induction of senescence

P38-Mediated Cellular Senescence in Conjunctivochalasis Fibroblasts

Oxidative Stress and Cellular Response to Doxorubicin: A Common Factor in the Complex Milieu of Anthracycline Cardiotoxicity

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