Inhibition of Fatty Acid Synthase Reduces Blastocyst Hatching through Regulation of the AKT Pathway in Pigs

Guo, Jing; Kim, Nam‐Hyung; Cui, Xiang‐Shun

doi:10.1371/journal.pone.0170624

Cited by 11 publications

(15 citation statements)

References 46 publications

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“…The level of TIP47, a marker for lipid droplets [ 24 ], was also higher in more resistant models (Figure 3A ). Pharmacological inhibition of FASN leads to a decrease in activation of pAkt [ 20 , 25 , 26 ]. However, inhibition of FASN also induces pro-survival Akt and ERK signaling in K-Ras-driven cancer cells [ 27 ].…”

Section: Resultsmentioning

confidence: 99%

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer

et al. 2018

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Fatty Acid Synthase (FASN), a key enzyme of de novo lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity in vitro and in vivo and a favorable tolerability profile in a Phase I clinical trial.However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood. We evaluated the effect of TVB-3664 on tumor growth in nine CRC patient-derived xenografts (PDXs) and investigated molecular and metabolic changes associated with CRC responsiveness to FASN inhibition.CRC cells and PDXs showed a wide range of sensitivity to FASN inhibition. TVB-3664 treatment showed significant response (reduced tumor volume) in 30% of cases. Anti-tumor effect of TVB-3664 was associated with a significant decrease in a pool of adenine nucleotides and alterations in lipid composition including a significant reduction in fatty acids and phospholipids and an increase in lactosylceramide and sphingomyelin in PDXs sensitive to FASN inhibition. Moreover, Akt, Erk1/2 and AMPK were major oncogenic pathways altered by TVBs.In summary, we demonstrated that novel TVB inhibitors show anti-tumor activity in CRC and this activity is associated with a decrease in activation of Akt and Erk1/2 oncogenic pathways and significant alteration of lipid composition of tumors. Further understanding of genetic and metabolic characteristics of tumors susceptible to FASN inhibition may enable patient selection and personalized medicine approaches in CRC.

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Section: Resultsmentioning

confidence: 99%

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer

et al. 2018

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“…Furthermore, the quality of blastocysts can be significantly affected by the treatments during the process of IVM [44]. In this regard, the TUNEL assay is universally used to detect DNA fragmentation and apoptosis in cells and, hence, evaluate the quality of preimplantation embryos [15,30]. In the current study, blastocysts corresponding to the group of low NAM exposure setting exhibited normal morphology with a significant increase in the total number of cells and lower incidence of DNA fragmentation, whereas the opposite profile was observed in the high NAM concentration group, confirming the data on apoptosis and autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, supplementation of IVM medium with the SIRT1 activator resveratrol improved the quality and the hatching of blastocysts [3]. On the other hand, Riley et al reported that inhibition of AKT significantly affected the normal physiology and hatching of blastocysts [22], while silencing the function of fatty acid synthase, an essential enzyme catalyze biogenesis of fatty acids, negatively influenced the hatching of embryos mainly through the downregulation of AKT [30]. Importantly, the activation of AKT/mTOR signaling in mouse oocytes and primordial follicles following the administration of resveratrol, an SIRT1 activator, was reported [19].…”

Section: Discussionmentioning

confidence: 99%

“…This precisely regulated process, the hatching, is crucial for survival, normal development, and implantation of embryos [ 28 , 29 ]. The critical roles of SIRT1 and AKT signaling in controlling the hatching process were reported [ 3 , 22 , 30 ]. Although the crosstalk between NAM and SIRT1/AKT was elucidated in different cancer cells [ 31 , 32 ], the potential linkage in the context of preimplantation embryo development is not yet reported.…”

Section: Introductionmentioning

confidence: 99%

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Nicotinamide Supplementation during the In Vitro Maturation of Oocytes Improves the Developmental Competence of Preimplantation Embryos: Potential Link to SIRT1/AKT Signaling

Sheikh

Mesalam

Idrees

et al. 2020

Cells

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Nicotinamide (NAM), the amide form of vitamin B3, plays pivotal roles in regulating various cellular processes including energy production and maintenance of genomic stability. The current study aimed at deciphering the effect of NAM, when administered during in vitro maturation (IVM), on the developmental competence of bovine preimplantation embryos. Our results showed that low NAM concentrations reduced the oxidative stress and improved mitochondrial profile, total cleavage and 8–16 cell stage embryo development whereas the opposite profile was observed upon exposure to high NAM concentrations (10 mM onward). Remarkably, the hatching rates of day-7 and day-8 blastocysts were significantly improved under 0.1 mM NAM treatment. Using RT-qPCR and immunofluorescence, the autophagy-related (Beclin-1 (BECN1), LC3B, and ATG5) and the apoptotic (Caspases; CASP3 and 9) markers were upregulated in oocytes exposed to high NAM concentration (40 mM), whereas only CASP3 was affected, downregulated, following 0.1 mM treatment. Additionally, the number of cells per blastocyst and the levels of SIRT1, PI3K, AKT, and mTOR were higher, while the inner cell mass-specific transcription factors GATA6, SOX2, and OCT4 were more abundant, in day-8 embryos of NAM-treated group. Taken together, to our knowledge, this is the first study reporting that administration of low NAM concentrations during IVM can ameliorate the developmental competence of embryos through the potential regulation of oxidative stress, apoptosis, and SIRT1/AKT signaling.

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“…Therefore, excessive ROS production has a negative effect on embryonic development (Bain, Madan, & Betts, ; Cebrian‐Serrano, Salvador, Raga, Dinnyes, & Silvestre, ). Previous studies have shown that inhibition of FAS can lead to ROS production, resulting in embryo arrest (Guo et al, ). In the present study, the results showed that FAS knockout could impair blastocyst hatching, but not blastocyst formation, via the generation of ROS.…”

Section: Discussionmentioning

confidence: 99%

Fatty acid synthase knockout impairs early embryonic development via induction of endoplasmic reticulum stress in pigs

Guo

Niu

Shin

et al. 2017

Journal Cellular Physiology

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Fatty acid synthase (FAS) is an important enzyme involved in the de novo synthesis of long-chain fatty acids. During development, the function of FAS in growth is greater than that in energy storage pathways; therefore, we hypothesized that knockout of FAS would affect early embryonic development owing to the induction of endoplasmic reticulum (ER) stress. In the present study, the function of FAS was studied using the CRISPR (clustered regularly interspaced short palindromic repeats)/ CRISPR-associated protein 9 (Cas9) system. Cas9 and single-guide RNA (sgRNA) were injected into parthenotes to decrease the number of FAS-positive embryos. The efficiency of knockout was assayed by DNA sequencing. We found that FAS knockout caused excessive production of reactive oxygen species (ROS). Excess ROS induced ER stress, resulting in activation of the adaptive unfolded protein response (UPR). FAS knockout caused splicing of the X-box binding protein 1 gene (XBP1) and expression of spliced XBP1 mRNA. In addition, FAS knockout caused phosphorylation of PKR-like ER kinase (PERK), and an increase in the mRNA expression of the ER stress-regulated genes, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). Finally, Ca was released from the ER and taken up by the mitochondria. As the ER stress became intolerable, apoptosis was initiated. These results demonstrate that FAS knockout induced ROS generation, which mediated the activation of UPR via the ER stress, ultimately leading to apoptosis induction.

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Inhibition of Fatty Acid Synthase Reduces Blastocyst Hatching through Regulation of the AKT Pathway in Pigs

Cited by 11 publications

References 46 publications

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer

Nicotinamide Supplementation during the In Vitro Maturation of Oocytes Improves the Developmental Competence of Preimplantation Embryos: Potential Link to SIRT1/AKT Signaling

Fatty acid synthase knockout impairs early embryonic development via induction of endoplasmic reticulum stress in pigs

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