scholarly journals The peroxisomal transporter ABCD3 plays a major role in dicarboxylic fatty acid metabolism

2021 ◽  
Author(s):  
Pablo Ranea-Robles ◽  
Hongjie Chen ◽  
Brandon Stauffer ◽  
Chunli Yu ◽  
Dipankar Bhattacharya ◽  
...  
Keyword(s):  
Fatty Acids ◽  
De Novo ◽  
Ketone Bodies ◽  
De Novo Lipogenesis ◽  
Lipid Homeostasis ◽  
Hepatic Cholesterol Synthesis ◽  
Specific Subset

Peroxisomes metabolize a specific subset of fatty acids, which include dicarboxylic fatty acids (DCAs) generated by ω-oxidation. Data obtained in vitro suggest that the peroxisomal transporter ABCD3 (also known as PMP70) mediates the transport of DCAs into the peroxisome, but in vivo evidence to support this role is lacking. In this study, we studied an Abcd3 KO mouse model generated by CRISPR-Cas9 technology using targeted and untargeted metabolomics, histology, immunoblotting, and stable isotope tracing technology. We show that ABCD3 functions in DCA metabolism and uncover a novel role for this peroxisomal transporter in lipid metabolic homeostasis. The Abcd3 KO mouse presents with lipodystrophy, increased circulating free fatty acids, decreased ketone bodies, enhanced hepatic cholesterol synthesis and decreased hepatic de novo lipogenesis. Moreover, our study suggests that DCAs are metabolized by mitochondrial β-oxidation when ABCD3 is not functional, reflecting the importance of the metabolic compartmentalization and communication between peroxisomes and mitochondria. In summary, this study provides data on the role of the peroxisomal transporter ABCD3 in hepatic lipid homeostasis and DCA metabolism, and the consequences of peroxisomal dysfunction for the liver.

Plasmalogens: targets for oxidants and major lipophilic antioxidants

2004 ◽  
Vol 32 (1) ◽  
pp. 147-150 ◽  
Author(s):  
B. Engelmann
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Lipid Oxidation ◽  
De Novo ◽  
Peroxyl Radicals ◽  
Plasma Lipoproteins ◽  
Future Work

Cellular membranes and plasma lipoproteins are less efficiently protected against oxidative stress than the various aqueous compartments of mammalian organisms. Here, previous results on the role of plasmalogens in lipid oxidation are evaluated on the basis of criteria required for an antioxidant. The plasmalogen-specific enol ether double bond is targeted by a vast variety of oxidants, including peroxyl radicals, metal ions, singlet oxygen and halogenating species. Oxidation of the vinyl ether markedly prevents the oxidation of highly polyunsaturated fatty acids, and products of plasmalogen degradation do not propagate lipid oxidation. This protection is also demonstrated intramolecularly, thus ascertaining the function of plasmalogens as a major storage pool for polyunsaturated fatty acids. Although cells rapidly incorporate and synthesize plasmalogens de novo, their plasmalogen contents can be deliberately increased by supplementation with precursors. Thus plasmalogens terminate lipid-oxidation processes, are present in adequate locations at sufficient concentrations, and are rapidly regenerated, classifying them as efficient antioxidants in vitro. Future work should address the in vivo role of plasmalogens in lipid oxidation and the biological function of plasmalogen interactions with oxidants.

scholarly journals Hepatic de novo lipogenesis is suppressed and fat oxidation is increased by omega-3 fatty acids at the expense of glucose metabolism

2020 ◽  
Vol 8 (1) ◽  
pp. e000871 ◽  
Author(s):  
Charlotte J Green ◽  
Camilla Pramfalk ◽  
Catriona A Charlton ◽  
Pippa J Gunn ◽  
Thomas Cornfield ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Plasma Glucose ◽  
De Novo ◽  
In Vitro Studies ◽  
De Novo Lipogenesis ◽  
Metabolic Effects ◽  
Omega 3 Fatty Acids ◽  
Omega 3

ObjectiveIncreased hepatic de novo lipogenesis (DNL) is suggested to be an underlying cause in the development of nonalcoholic fatty liver disease and/or insulin resistance. It is suggested that omega-3 fatty acids (FA) lower hepatic DNL. We investigated the effects of omega-3 FA supplementation on hepatic DNL and FA oxidation using a combination of human in vivo and in vitro studies.Research design and methodsThirty-eight healthy men were randomized to take either an omega-3 supplement (4 g/day eicosapentaenoic acid (EPA)+docosahexaenoic acid (DHA) as ethyl esters) or placebo (4 g/day olive oil) and fasting measurements were made at baseline and 8 weeks. The metabolic effects of omega-3 FAs on intrahepatocellular triacylglycerol (IHTAG) content, hepatic DNL and FA oxidation were investigated using metabolic substrates labeled with stable-isotope tracers. In vitro studies, using a human liver cell-line was undertaken to gain insight into the intrahepatocellular effects of omega-3 FAs.ResultsFasting plasma TAG concentrations significantly decreased in the omega-3 group and remained unchanged in the placebo group. Eight weeks of omega-3 supplementation significantly decreased IHTAG, fasting and postprandial hepatic DNL while significantly increasing dietary FA oxidation and fasting and postprandial plasma glucose concentrations. In vitro studies supported the in vivo findings of omega-3 FAs (EPA+DHA) decreasing intracellular TAG through a shift in cellular metabolism away from FA esterification toward oxidation.ConclusionsOmega-3 supplementation had a potent effect on decreasing hepatic DNL and increasing FA oxidation and plasma glucose concentrations. Attenuation of hepatic DNL may be considered advantageous; however, consideration is required as to what the potential excess of nonlipid substrates (eg, glucose) will have on intrahepatic and extrahepatic metabolic pathways.Trial registration numberNCT01936779.

scholarly journals Targeting Myeloma Cell Metabolism Via Disruption of the Lnc-17-92 Transcriptional Program: Druggable New Vulnerability in Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 317-317
Author(s):  
Eugenio Morelli ◽  
Mariateresa Fulciniti ◽  
Mehmet Kemal Samur ◽  
Caroline Ribeiro ◽  
Leon Wert-Lamas ◽  
...  
Keyword(s):  
Cell Growth ◽  
Transcriptional Control ◽  
De Novo ◽  
Cell Metabolism ◽  
Inhibitory Effect ◽  
Advisory Board ◽  
De Novo Lipogenesis

Long noncoding RNAs (lncRNA) are major regulators of chromatin dynamics and gene expression. We have recently performed deep RNA sequencing of CD138+ cells from 360 uniformly-treated, newly-diagnosed multiple myeloma (MM) patients (IFM/DFCI 2009) and described the lncRNA landscape and their role as independent risk predictors for clinical outcome in MM. Moreover, we have identified one of these lncRNAs - lnc-17-92 - as an independent risk predictor highly correlating with EFS and OS in newly-diagnosed MM providing rationale to define its molecular role in MM. Lnc-17-92 is generated at MIR17HG gene locus and is known for being involved in the biogenesis of miR-17-92 cluster of microRNAs. We here establish, for the first time, role of this transcript as a lncRNA with microRNA-independent function and molecular and biological implications in MM. Having confirmed its expression in MM cell lines and primary MM cells, we have utilized antisense oligonucleotides (n=3) to suppress lnc-17-92 expression in large panel of human MM cell lines (HMCLs) (n=12) and primary patient MM cells (n=13). Lnc-17-92 inhibition impaired MM cell proliferation leading to apoptotic cell death. This inhibitory effect was not rescued by ectopic expression of miR-17-92 microRNAs, confirming independent activity of lnc-17-92 on MM cell growth and viability. The microRNA-independent role of lnc-17-92 in transcriptional control was further confirmed using DROSHAKOcells. Analysis of transcriptomic changes after lnc-17-92 modulation in HMCLs and primary MM cells identified bona fide transcriptional targets of lnc-17-92. Using two independent MM RNA-seq datasets, we observed high correlation (R> 0.4) between lnc-17-92 expression and the expression of 12 of the transcriptional targets identified above. Interestingly, these genes were significantly enriched within metabolic pathways, suggesting an unexplored role for lnc-17-92 in MM cell metabolism. Further analysis using an RNAi-based loss-of-function screening in 3 HMCLs revealed Acetyl-CoA Carboxylase Alpha (ACC1) as a novel myeloma vulnerability. ACC1 encodes the limiting enzyme in the de novo lipogenesis pathway. Analysis of incorporation of C14-radiolabeled glucose into lipids in MM cells revealed that inhibition of ACC1 or lnc-17-92 strongly inhibited de novo lipogenesis in HMCLs and in primary MM cells. We have used ACC1 conditional KD MM cells expressing IPTG-inducible ACC1 shRNAs and confirmed significant role of ACC1 in MM cell growth and survival, both in vitro and in vivo in SCID mice model. Importantly, supplementation of palmitate, the main downstream product of ACC1 activity, significantly reverses the growth inhibitory effect of either ACC1 or lnc-17-92 suppression in MM cells. These data suggest an important role for lipogenesis pathway on lnc-17-92-promoted MM cell growth. We have further investigated mechanism by which lnc-17-92 may exert its transcriptional control. Protein-RNA pulldown assay established MYC as interacting partner of lnc-17-92. This interaction was confirmed by immunoprecipitation of MYC-bound RNA followed by qRT-PCR with specific primers for detection of lnc-17-92. ChIP-seq analysis revealed a direct binding of MYC at regulatory regions of ACC1 in MM.1S cells; these data were corroborated by the decreased ACC1 expression observed in MYC KD MM cells. Taken together, these data suggest that lnc-17-92 may function as a scaffold between MYC and the E-box motifs present on ACC1 intronic sequences, facilitating MYC binding and its transcriptional activity on ACC1. Finally, for translational application, we have pre-clinically investigated ND-646, a clinically applicable small molecule inhibitor of ACC1. Analysis of incorporation of C14-radiolabeled glucose into lipids confirmed its effect on lipogenesis in MM, which was associated with a significant in vitro growth inhibitory activity in large panel of HMCLs and primary patient MM cells. In vivo studies in murine model of human MM, using this oral agent, are ongoing and will be presented. In conclusion, we here report for the first time the microRNA-independent role of lnc-17-92 in MM pathobiology with direct impact on transcriptional control of lipogenesis. The availability of oral inhibitor of this pathway may allow the clinical application of this unique targeted therapy in MM. Disclosures Anderson: Janssen: Other: Advisory Board; Gilead Sciences: Other: Advisory Board; OncoPep: Other: Scientific founder ; Sanofi-Aventis: Other: Advisory Board; C4 Therapeutics: Other: Scientific founder . Munshi:Abbvie: Consultancy; Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Adaptive: Consultancy; Oncopep: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Oncopep: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Abbvie: Consultancy.

HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming

2021 ◽  
Author(s):  
Xiaodong Lu ◽  
Ka-wing Fong ◽  
Fang Wang ◽  
Galina Gritsina ◽  
Sylvan C. Baca ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Xenograft Tumor ◽  
Dna Hypermethylation ◽  
Castration Resistant

ABSTRACTHOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) function and promotes androgen-dependent prostate cancer (PCa) growth. However, the functions of HOXB13 in an AR-independent context remain elusive. Here we report an essential role of HOXB13 in directly suppressing lipogenic transcriptional programs in both AR-positive and -negative PCa cells. The MEIS domain (aa70-150) of HOXB13 interacts with the histone deacetylase HDAC3, which is disrupted by HOXB13 G84E mutation that has been associated with early-onset PCa. Thus, HOXB13 wildtype (WT), but not G84E mutant, recruits HDAC3 to lipogenic enhancers to catalyze histone de-acetylation and suppress lipogenic programs. HOXB13 knockdown unleashes the expression of key lipogenic regulators such as fatty acid synthase (FASN), requiring HDAC3. Analysis of human tissues revealed that HOXB13 is lost in about 30% of metastatic castration-resistant PCa, at least in part, through DNA hypermethylation. Functionally, loss of HOXB13 leads to massive lipid accumulation in PCa cells, thereby promoting cell motility in vitro and fueling xenograft tumor metastasis in vivo, which is mitigated by pharmaceutical inhibitors of FASN. In summary, our study discovers an essential AR-independent function of HOXB13 in repressing de novo lipogenesis and inhibiting tumor metastasis and defines a subclass of PCa that may benefit from lipogenic pathway inhibitors.

scholarly journals Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer

2021 ◽  
Author(s):  
Caterina Bartolacci ◽  
Cristina Andreani ◽  
Goncalo Dias do Vale ◽  
Stefano Berto ◽  
Margherita Melegari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Fatty Acid ◽  
Metabolic Networks ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Genetically Engineered ◽  
De Novo Lipogenesis ◽  
Main Process

Mutant KRAS (KM) is the most common oncogene in lung cancer (LC). KM regulates several metabolic networks, but their role in tumorigenesis is still not sufficiently characterized to be exploited in cancer therapy. To identify metabolic networks specifically deregulated in KMLC, we characterized the lipidome of genetically engineered LC mice, cell lines, patient derived xenografts and primary human samples. We also determined that KMLC, but not EGFR-mutant (EGFR-MUT) LC, is enriched in triacylglycerides (TAG) and phosphatidylcholines (PC). We also found that KM upregulates fatty acid synthase (FASN), a rate-limiting enzyme in fatty acid (FA) synthesis promoting the synthesis of palmitate and PC. We determined that FASN is specifically required for the viability of KMLC, but not of LC harboring EGFR-MUT or wild type KRAS. Functional experiments revealed that FASN inhibition leads to ferroptosis, a reactive oxygen species (ROS)-and iron-dependent cell death. Consistently, lipidomic analysis demonstrated that FASN inhibition in KMLC leads to accumulation of PC with polyunsaturated FA (PUFA) chains, which are the substrate of ferroptosis. Integrating lipidomic, transcriptome and functional analyses, we demonstrated that FASN provides saturated (SFA) and monounsaturated FA (MUFA) that feed the Lands cycle, the main process remodeling oxidized phospholipids (PL), such as PC. Accordingly, either inhibition of FASN or suppression of the Lands cycle enzymes PLA2 and LPCAT3, promotes the intracellular accumulation of lipid peroxides and ferroptosis in KMLC both in vitro and in vivo. Our work supports a model whereby the high oxidative stress caused by KM dictates a dependency on newly synthesized FA to repair oxidated phospholipids, establishing a targetable vulnerability. These results connect KM oncogenic signaling, FASN induction and ferroptosis, indicating that FASN inhibitors already in clinical trial in KMLC patients (NCT03808558) may be rapidly deployed as therapy for KMLC.

scholarly journals Cytoplasmic Expression of the ALS/FTD-Related Protein TDP-43 Decreases Global Translation Both in vitro and in vivo

2020 ◽  
Vol 14 ◽  
Author(s):  
Santiago E. Charif ◽  
Luciana Luchelli ◽  
Antonella Vila ◽  
Matías Blaustein ◽  
Lionel M. Igaz
Keyword(s):  
De Novo ◽  
Brain Slices ◽  
Mrna Translation ◽  
Hek293 Cells ◽  
Cytoplasmic Inclusions ◽  
Cytoplasmic Expression ◽  
Global Translation

TDP-43 is a major component of cytoplasmic inclusions observed in neurodegenerative diseases like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). To further understand the role of TDP-43 in mRNA/protein metabolism and proteostasis, we used a combined approach with cellular and animal models overexpressing a cytoplasmic form of human TDP-43 (TDP-43-ΔNLS), recapitulating ALS/FTD features. We applied in HEK293 cells a method for labeling de novo translation, surface sensing of translation (SUnSET), based on puromycin (PURO) incorporation. While control cells displayed robust puromycilation, TDP-43-ΔNLS transfected cells exhibited reduced ongoing protein synthesis. Next, by using a transgenic mouse overexpressing cytoplasmic TDP-43 in the forebrain (TDP-43-ΔNLS mice) we assessed whether cytoplasmic TDP-43 regulates global translation in vivo. Polysome profiling of brain cortices from transgenic mice showed a shift toward non-polysomal fractions as compared to wild-type littermates, indicating a decrease in global translation. Lastly, cellular level translational assessment by SUNSET was performed in TDP-43-ΔNLS mice brain slices. Control mice slices incubated with PURO exhibited robust cytoplasmic PURO signal in layer 5 neurons from motor cortex, and normal nuclear TDP-43 staining. Neurons in TDP-43-ΔNLS mice slices incubated with PURO exhibited high cytoplasmic expression of TDP-43 and reduced puromycilation respect to control mice. These in vitro and in vivo results indicate that cytoplasmic TDP-43 decreases global translation and potentially cause functional/cytotoxic effects as observed in ALS/FTD. Our study provide in vivo evidence (by two independent and complementary methods) for a role of mislocalized TDP-43 in the regulation of global mRNA translation, with implications for TDP-43 proteinopathies.

Lipid Labelling in Intact Chloroplasts from Exogenous Nucleotide Precursors

1981 ◽  
Vol 36 (1-2) ◽  
pp. 62-70 ◽  
Author(s):  
Margrit Bertrams ◽  
Käthe Wrage ◽  
Ernst Heinz
Keyword(s):  
Fatty Acids ◽  
Free Fatty Acids ◽  
De Novo ◽  
Membrane System ◽  
Chloroplast Envelope ◽  
Label Free ◽  
Intact Chloroplasts ◽  
Time Required

Abstract De novo-synthesis of glycerolipids in chloroplasts is initiated by a stroma enzyme which catalyzes the formation of lyso-phosphatidic acid from glycerophosphate and acyl-CoA. When these substrates are added to isolated, intact chloroplasts, only glycerophosphate can readily pass through the chloroplast envelope which represents a permeation barrier for acyl-CoA, although higher thioester concentrations destroy this membrane system. At low concentrations of acyl-CoA, which do not impair the envelope, intact chloroplasts metabolize exogenous acyl-CoA in two ways to give free fatty acids and labelled phosphatidyl choline. This indicates that the envelope thioesterase can use exogenous substrates. Isolated, intact chloroplasts fixing radioactive CO2 label free fatty acids and acylglycerols but not galactolipids, since they cannot convert 3-phosphoglycerate into UDP-galactose which in vivo is supplied by the cytoplasm. This cooperation was simulated in vitro by adding all enzymes and cofactors necessary for conversion of 3-phosphoglycerate into UDP-galactose to intact chloro­plasts which then formed labelled monogalactosyl diacylglycerol from labelled CO2. The time required to transfer envelope-made galactolipids from the envelope into thylakoids was studied by incubating intact chloroplasts with radioactive UDP-galactose, subsequent osmotic disruption of organelles with concomitant enzymatic degradation of UDP-galactose followed by separation of envelopes and thylakoids. Only after short times (< 1min) appreciable proportions 920-30%) of radioactive galactolipid export from envelopes into thylakoids.

The Role of Nucleophosmin In Hematopoietic Stem Cells and the Pathogenesis of Myelodysplastic Syndrome

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Keisuke Ito ◽  
Paolo Sportoletti ◽  
John G Clohessy ◽  
Grisendi Silvia ◽  
Pier Paolo Pandolfi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Cell Biology ◽  
De Novo ◽  
Stem Cell Biology ◽  
Hematopoietic Stem

Abstract Abstract 95 Myelodysplastic syndrome (MDS) is an incurable stem cell disorder characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Nucleophosmin (NPM) is directly implicated in primitive hematopoiesis, the pathogenesis of hematopoietic malignancies and more recently of MDS. However, little is known regarding the molecular role and function of NPM in MDS pathogenesis and in stem cell biology. Here we present data demonstrating that NPM plays a critical role in the maintenance of hematopoietic stem cells (HSCs) and the transformation of MDS into leukemia. NPM is located on chromosome 5q and is frequently lost in therapy-related and de novo MDS. We have previously shown that Npm1 acts as a haploinsufficient tumor suppressor in the hematopoietic compartment and Npm1+/− mice develop a hematologic syndrome with features of human MDS, including increased susceptibility to leukemogenesis. As HSCs have been demonstrated to be the target of the primary neoplastic event in MDS, a functional analysis of the HSC compartment is essential to understand the molecular mechanisms in MDS pathogenesis. However, the role of NPM in adult hematopoiesis remains largely unknown as Npm1-deficiency leads to embryonic lethality. To investigate NPM function in adult hematopoiesis, we have generated conditional knockout mice of Npm1, using the Cre-loxP system. Analysis of Npm1 conditional mutants crossed with Mx1-Cre transgenic mice reveals that Npm1 plays a crucial role in adult hematopoiesis and ablation of Npm1 in adult HSCs leads to aberrant cycling and followed by apoptosis. Analysis of cell cycle status revealed that HSCs are impaired in their ability to maintain quiescence after Npm1-deletion and are rapidly depleted in vivo as well as in vitro. Competitive reconstitution assay revealed that Npm1 acts cell-autonomously to maintain HSCs. Conditional inactivation of Npm1 leads to an MDS phenotype including a profoundly impaired ability to differentiate into cells of the erythroid lineage, megakaryocyte dyspoiesis and centrosome amplification. Furthermore, Npm1 loss evokes a p53-dependent response and Npm1-deleted HSCs undergo apoptosis in vivo and in vitro. Strikingly, transfer of the Npm1 mutation into a p53-null background rescued the apoptosis of Npm1-ablated HSCs and resulted in accelerated transformation to an aggressive and lethal form of acute myeloid leukemia. Our findings highlight the crucial role of NPM in stem cell biology and identify a new mechanism by which MDS can progress to leukemia. This has important therapeutic implications for de novo MDS as well as therapy-related MDS, which is known to rapidly evolve to leukemia with frequent loss or mutation of TRP53. Disclosures: No relevant conflicts of interest to declare.

L-arginine depletion by PEG-arginase I, a new potential therapy for acute lymphoblastic leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6580-6580
Author(s):  
Ofelia Crombet Ramos ◽  
Claudia Hernandez ◽  
Kevin Morrow ◽  
John T. Cole ◽  
Paulo Rodriguez
Keyword(s):  
Cell Proliferation ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
De Novo ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Arginase I

6580 Background: Advances in therapies have resulted in an overall complete remission rate of approximately 85% for childhood acute lymphoblastic leukemia (ALL). In contrast, the overall remission rate of adults with leukemia continues to be poor, only about 40% in cases of T cell-ALL (T-ALL). Therefore, it is imperative to generate new therapies that alone or in combination with other treatments could potentially increase the percentages of complete responders or be used to treat the refractory ALL population. Our published results show that a pegylated form of human arginase I (peg-Arg I) prevented T-ALL cell proliferation in vitro and in vivo through the induction of tumor cell apoptosis. Interestingly, the anti-leukemic effects induced by peg-Arg I did not affect the anti-tumor activity of normal T cells, suggesting an anti-tumor specific effect. Our hypothesis states that peg-Arg I has an anti-tumoral effect on B-ALL and T-ALL cells in vitro and that the sensitivity of ALL cells to peg-Arg I depends on their expression of argininosuccinate synthase (ASS) and their ability to produce L-arginine de novo from citrulline. Methods: Malignant T cell proliferation was tested using nonradioactive cell proliferation yellow tretrazolium salt kit. Apoptosis studies were based on the expression of annexin V. Western blot assays were conducted to determine enzymatic expression in different cell lines. Results: The results of our in vitro experiments showed that peg-Arg I had a pro-apoptotic and anti-proliferattive effect on B-ALL cells similar to the one previously seen on T-ALL cells. These effects can be overcome in cell lines able that express ASS and therefore to produce L-arginine de novo. Conclusions: Our results suggest the role of ASS in the ALL-apoptosis induced by peg-Arg-I. Our next steps include: _Understand why ASS-expressing ALL cells do not undergo apoptosis when cultured with peg-Arg-I_Determine the role of ASS in the anti-leukemic effect induced by peg-Arg-I in vivo. Completion of this research is expected to lead to a better understanding of how peg-Arg-I kills ALL cells and could provide the foundation for a novel therapy for ALL patients.

scholarly journals Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis

2020 ◽  
Vol 21 (22) ◽  
pp. 8467
Author(s):  
Jiaoyuan Jia ◽  
Li Che ◽  
Antonio Cigliano ◽  
Xue Wang ◽  
Graziella Peitta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Liver Tumors ◽  
Cellular Growth ◽  
De Novo Lipogenesis ◽  
Liver Malignancy ◽  
Genetic Ablation

Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.

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