Regulation of lipids is central to replicative senescence

Lizardo, Darleny Y.; Lin, Yen-Lung; Gökçümen, Ömer; Atilla‐Gokcumen, G. Ekin

doi:10.1039/c6mb00842a

Cited by 78 publications

(82 citation statements)

References 61 publications

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“…We followed similar lipidomics workflow as how we described in the past for sample preparation, data acquisition, and analysis. [ 8,11,20 ] Briefly, five biological replicates of proliferating and senescent cells were analyzed in positive and negative electrospray ionization modes. Peak alignment based on mass‐to‐charge ratio ( m / z ), grouping of different adducts, retention time, and isotopic ratio was carried out in Profinder (Agilent Technologies).…”

Section: Resultsmentioning

confidence: 99%

“…LC‐MS analysis was performed as described previously. [ 8,11,20 ] Briefly, LC‐MS data acquisition was performed using an Agilent 1260 HPLC paired with an Agilent 6530 Accurate‐Mass Quadrupole Time‐of‐Flight mass spectrometer (Agilent Technologies, Santa Clara, CA). Prior to analysis, separation was achieved with reverse phase chromatography.…”

Section: Methodsmentioning

confidence: 99%

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Untargeted Lipidomics Highlight the Depletion of Deoxyceramides during Therapy‐Induced Senescence

2020

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Therapy-induced senescence is a state of cell cycle arrest that occurs as a response to various chemotherapeutic reagents, especially ones that cause DNA damage. Senescent cells display resistance to cell death and can impair the efficacy of chemotherapeutic strategies. Since lipids can exhibit pro-survival activity, it is envisioned in this article that probing the lipidome could provide insights into novel lipids that are involved in senescence. Therefore, a tissue culture model system is established and the cellular lipidomes of senescent and proliferating cells are comparatively analyzed. Out of thousands of features detected, 17 species are identified that show significant changes in senescent cells. The majority of these species (11 out of 17) are atypical sphingolipids, 1-deoxyceramides/dihydroceramides, which are produced as a result of the utilization of alanine, instead of serine during sphingolipid biosynthesis. These lipids are depleted in senescent cells. Elevating the levels of deoxyceramides by supplementing the growth medium with metabolic precursors or by directly adding deoxyceramide result in decreased senescence, suggesting that these species might play a key role in this process.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Untargeted Lipidomics Highlight the Depletion of Deoxyceramides during Therapy‐Induced Senescence

2020

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“…As accumulation of triacylglycerol (TG) is central to replicative senescence (33), we also performed senescence-associated(SA)- b-Gal staining on all six groups [Control, Tg(Wnt), Tg(Myc), Tg(Kras), Tg(Wnt&Kras), Tg(Myc&Kras)], and found that Tg(Kras), but not Tg(Wnt) or Tg(Myc), induced notable cell senescence in the liver; senescence was significantly alleviated in Tg(Wnt&Kras) and Tg(Myc&Kras) ( Fig. 3C; Supplementary Fig.…”

Section: Wnt/myc Activity Represses the Extensive Hepatic Steatosis Amentioning

confidence: 99%

Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult

et al. 2018

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There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human and zebrafish or murine together with in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by expression alone. UPLC-MS-based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention. These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma. http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg .

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“…4) (42,79,80,117). As first observed using microarrays, CD36 mRNA expression is induced in senescent cells as member of a number of lipid-regulating genes possibly leading to accumulation of ceramides and triacylglycerols with long and very long unsaturated fatty acyl side chains (259,260). Recent studies suggest that during senescence, CD36 up-regulation is an important event in initiating the SASP, in activating of the Src/p38/NFκB pathway and of lysosomal senescence-associated β-galactosidase expression in response to senescent stimuli such as βA (259,261).…”

Section: Modulation Of Signaling Pathways By Vitamin E Relevant To Cementioning

confidence: 83%

Vitamin E: Regulatory Role on Signal Transduction

Zingg

2018

IUBMB Life

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Vitamin E modulates signal transduction pathways by several molecular mechanisms. As a hydrophobic molecule located mainly in membranes it contributes together with other lipids to the physical and structural characteristics such as membrane stability, curvature, fluidity, and the organization into microdomains (lipid rafts). By acting as the main lipid‐soluble antioxidant, it protects other lipids such as mono‐ and poly‐unsaturated fatty acids (MUFA and PUFA, respectively) against chemical reactions with reactive oxygen and nitrogen species (ROS and RNS, respectively) and prevents membrane destabilization and cellular dysfunction. In cells, vitamin E affects signaling in redox‐dependent and redox‐independent molecular mechanisms by influencing the activity of enzymes and receptors involved in modulating specific signal transduction and gene expression pathways. By protecting and preventing depletion of MUFA and PUFA it indirectly enables regulatory effects that are mediated by the numerous lipid mediators derived from these lipids. In recent years, some vitamin E metabolites have been observed to affect signal transduction and gene expression and their relevance for the regulatory function of vitamin E is beginning to be elucidated. In particular, the modulation of the CD36/FAT scavenger receptor/fatty acids transporter by vitamin E may influence many cellular signaling pathways relevant for lipid homeostasis, inflammation, survival/apoptosis, angiogenesis, tumorigenesis, neurodegeneration, and senescence. Thus, vitamin E has an important role in modulating signal transduction and gene expression pathways relevant for its uptake, distribution, metabolism, and molecular action that when impaired affect physiological and patho‐physiological cellular functions relevant for the prevention of a number of diseases. © 2018 IUBMB Life, 71(4):456–478, 2019

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Regulation of lipids is central to replicative senescence

Cited by 78 publications

References 61 publications

Untargeted Lipidomics Highlight the Depletion of Deoxyceramides during Therapy‐Induced Senescence

Untargeted Lipidomics Highlight the Depletion of Deoxyceramides during Therapy‐Induced Senescence

Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult

Vitamin E: Regulatory Role on Signal Transduction

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