scholarly journals Acquired deficiency of the peroxisomal enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase is a metabolic vulnerability in hepatoblastoma

2020 ◽  
Author(s):  
Huabo Wang ◽  
Xiaoguang Chen ◽  
Marie Schwalbe ◽  
Joanna E. Gorka ◽  
Jordan A. Mandel ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Intracellular Transport ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Small Magnitude ◽  
Peroxisomal Enzyme ◽  
Human Cancers ◽  
Hydroxyacyl Coa Dehydrogenase ◽  
Pathway Inhibition ◽  
Enoyl Coa Hydratase

AbstractMetabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial β- and peroxisomal ω-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.

scholarly journals 616 CD47 blockade modulates immunosuppressive checkpoint molecules and cellular metabolism to sensitize triple-negative breast cancer tumors to immune checkpoint blockade therapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A646-A646
Author(s):  
Elizabeth Stirling ◽  
Adam Wilson ◽  
Katherine Cook ◽  
Alexandra Thomas ◽  
Pierre Triozzi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
Triple Negative Breast Cancer ◽  
Immune Checkpoint ◽  
Triple Negative ◽  
Immune Cell ◽  
Tumor Burden ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Immunosuppressive Cell

BackgroundTriple-negative breast cancer(TNBC) lacks druggable targets and has high metastatic incidence. Immune checkpoint blockades (ICB) are FDA approved for TNBC treatment, but therapeutic response and biomarkers are limited. CD47 is an integral membrane protein overexpressed on cancer cells that alters anti-tumor immunosurveillance, resulting in tumor progression. CD47 is involved in metabolic reprogramming but whether CD47 is a marker of progression and its role in ICB response for TNBC remains unknown.MethodsHuman TNBC biopsies were subjected to immunohistochemical analysis to determine CD47 role in TNBC progression. To determine CD47 impact on tumor burden, a carcinogen-induced TNBC model was performed in female wild type(WT) and cd47 null(cd47-/-) C57Bl/6 mice. To evaluate immune infiltrate signaling, tumors underwent spatial tissue proteomics by multiplexing photo-cleavable antibodies in Formalin-Fixed Paraffin-Embedded samples. An orthotopic EMT-6 murine TNBC model was performed to investigate tumor burden for CD47 monotherapy or in combination with anti-PD-L1 therapy.ResultsHuman matched primary, and metastatic TNBC biopsies increased immunoreactivity to CD47, signifying a potential therapeutic target(n=24). CD47 deficiency in the carcinogen-induced DMBA model decreased tumor incidence, weight, and area compared to WT(n=8/group,*p<0.003). Since CD47 can regulate metabolism, tumors underwent metabolomic analysis. Principal component analysis displayed differentially regulated metabolites between WT and cd47-/- tumors. Decreased carnitine conjugated fatty acids and ketone bodies were observed in cd47-/- tumors compared to WT, suggesting decreased fatty acid availability and/or metabolism(n=9/group,*p<0.05). TNBC cell respiratory measurements validated that targeting CD47 shifted metabolic dependency from fatty acid oxidation to glycolysis(n=3,*p<0.05). Kynurenine/tryptophan pathway metabolites, which catabolize Indoleamine-2,3-dioxygenase(IDO1) and involved in anti-PD-1/PD-L1 resistance, were decreased in cd47-/- tumors compared to WT(n=9/group,*p<0.05). Spatial proteomic analysis determined that cd47-/- tumors had elevated immune cell infiltration(CD45+, CD3+), suggesting CD47 absence enhances tumor immunogenicity and immune-mediated tumor ablation. Multiplexing of photo-cleavable antibodies increased protein expression of immune checkpoint molecules(PD-L1,VISTA,B7-H3,BatF3) and immunosuppressive cell types(CD11b+,Ly6c+) in WT tumors compared to cd47-/-, suggesting CD47 absence limits immunosuppressive signaling(n=16/group,*p<0.05). Since anti-PD-L1 therapies are approved to treat TNBC and WT tumors have PD-L1 upregulation, we examined how targeting CD47 would impact tumor burden of mice receiving anti-PD-L1 therapy. Targeting CD47 or PD-L1 as monotherapy decreased tumor burden; however, in combination it further reduced tumor burden compared to anti-PD-L1 treatment due to increased intratumoral granzyme B secreting cytotoxic T cells(n=4–8/group,*p<0.05).ConclusionsOur data indicates that CD47 may serve as a marker of anti-PD-L1 response, and targeting CD47 enhances immunogenicity and decreases immunosuppressive molecules, sensitizing TNBC tumors to anti-PD-L1 therapy to reduce tumor burden.AcknowledgementsDSP is supported by the NCI R21 (CA249349) and the American Cancer Society Research Scholar Grant (133727-RSG-19-150-01-LIB). ERS is supported by the NIAID Immunology and Pathogenesis T32 Training Grant (T32AI007401).Ethics ApprovalAnimal studies were approved by the Institutional Care and Use Committee, Wake Forest Health Sciences.

High PRMT1 Expression Promotes the Progression of Acute Megakaryocytic Leukemia Via Controlling Metabolic Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1551-1551
Author(s):  
Hairui Su ◽  
Han Guo ◽  
Ngoc-Tung Tran ◽  
Minkui Luo ◽  
Xinyang Zhao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Pathways ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Epigenetic Changes ◽  
Acute Megakaryocytic Leukemia ◽  
Megakaryocyte Differentiation

Abstract Metabolic reprogramming is needed not only to accommodate but also to drive leukemia progression. Yet very little is known on genetic factors other than IDH1 mutations, which can drive leukemogenesis via metabolic reprogramming. Here, we will present data to suggest that protein arginine methyltransferases 1 (PRMT1) is a driver for acute megakaryocytic leukemia via reprogramming metabolism. PRMT1 is highly expressed in megakaryocyte-erythrocyte progenitor cells and downregulated during the terminal differentiation of megakaryocytes. Constitutively high expression of PRMT1 in acute megakaryoblastic leukemia (AMKL) blocks megakaryocyte differentiation. PRMT1 upregulates RBM15 protein level via methylation-dependent ubiquitylation pathway (Zheng et al. Elife, 2015). In this presentation, we discovered that metabolic stress such as hypoxia downregulates PRMT1 protein level. Thus, metabolic stress is the upstream signal for the PRMT1-RBM15 pathway. We have identified that RBM15 specifically binds to 3'UTR of mRNAs of genes involved in metabolic pathways. Using RNA-immunoprecipitation with anti-RBM15 antibody and real-time PCR assays, we validated that RBM15 binds to mRNAs of genes involved in fatty acid oxidation and glycolysis. We transduced PRMT1 into an RBM15-MKL1 expressing cell line 6133. Overexpression of PRMT1 renders 6133 cells to grow in a cytokine-independent manner with increased mitochondria biogenesis, which in turn produces higher concentration of ATP in our metabolomic analysis. Based on the analysis of metabolomics data and RBM15-target genes, we conclude that PRMT1 promotes the usage of glucose as bioenergy via oxidative phosphorylation and inhibits fatty acid oxidation. Given that acetyl-coA is higher in PRMT1 expressing 6133 cells, we asked whether histone acetylation is upregulated in PRMT1 overexpressed 6133 cells. Indeed, we found higher histone acetylation level in PRMT1 highly expressed cells. We also found that propionylated histone is reduced, which is consistent with reduced fatty acid oxidation. Propionyl-CoA molecules are produced from fatty acids with odd carbon numbers. Thus PRMT1-mediated metabolic reprogramming changes epigenetic programming during leukemia progression. Intriguing, we also found PRMT1 overexpression enhances histone H3S10 phosphorylation via methylation-dependent ubiquitylation of DUSP4. DUSP4 promotes polyploidy during megakaryocyte differentiation. Thus PRMT1 caused profound epigenetic changes to promote leukemogenesis. In this vein, we established mouse AMKL models by bone marrow transplantation of 6133 cells as well as human AMKL patient samples respectively. Using this mouse model, we tested PRMT1 inhibitors, acetyltransferase inhibitors as well as other metabolic inhibitors. Treating cells with PRMT1 inhibitors as well as metabolic inhibitors promote MK differentiation of AMKL leukemia cells. Metabolomics analysis of cells recovered from mouse models will be discussed in the presentation. In summary, our data demonstrated that PRMT1 is a major sensor for metabolic stress and that PRMT1 in turn reprograms metabolic pathways to bring epigenetic changes in leukemogenesis. Therefore, targeting PRMT1 and downstream PRMT1-regulated metabolic pathways will offer new avenues in treating acute megakaryocytic leukemia and other hematological malignancies with defective megakaryocyte differentiation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Effects of Fatty Acid Oxidation and Its Regulation on Dendritic Cell-Mediated Immune Responses in Allergies: An Immunometabolism Perspective

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Shanfeng Sun ◽  
Yanjun Gu ◽  
Junjuan Wang ◽  
Cheng Chen ◽  
Shiwen Han ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Fatty Acid ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Fatty Acid Oxidation ◽  
Cell Activation ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Dendritic Cell Activation ◽  
Functional Changes

Type 1 allergies, involve a complex interaction between dendritic cells and other immune cells, are pathological type 2 inflammatory immune responses against harmless allergens. Activated dendritic cells undergo extensive phenotypic and functional changes to exert their functions. The activation, differentiation, proliferation, migration, and mounting of effector reactions require metabolic reprogramming. Dendritic cells are important upstream mediators of allergic responses and are therefore an important effector of allergies. Hence, a better understanding of the underlying metabolic mechanisms of functional changes that promote allergic responses of dendritic cells could improve the prevention and treatment of allergies. Metabolic changes related to dendritic cell activation have been extensively studied. This review briefly outlines the basis of fatty acid oxidation and its association with dendritic cell immune responses. The relationship between immune metabolism and effector function of dendritic cells related to allergic diseases can better explain the induction and maintenance of allergic responses. Further investigations are warranted to improve our understanding of disease pathology and enable new treatment strategies.

scholarly journals FABP3 Deficiency Exacerbates Metabolic Derangement in Cardiac Hypertrophy and Heart Failure via PPARα Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Lingfang Zhuang ◽  
Ye Mao ◽  
Zizhu Liu ◽  
Chenni Li ◽  
Qi Jin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cardiac Hypertrophy ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Transverse Aortic Constriction ◽  
Aortic Constriction ◽  
Metabolic Derangement ◽  
Fatty Acid Binding ◽  
Atp Production ◽  
Incidence And Mortality

Background: Cardiac hypertrophy was accompanied by various cardiovascular diseases (CVDs), and due to the high global incidence and mortality of CVDs, it has become increasingly critical to characterize the pathogenesis of cardiac hypertrophy. We aimed to determine the metabolic roles of fatty acid binding protein 3 (FABP3) on transverse aortic constriction (TAC)-induced cardiac hypertrophy.Methods and Results: Transverse aortic constriction or Ang II treatment markedly upregulated Fabp3 expression. Notably, Fabp3 ablation aggravated TAC-induced cardiac hypertrophy and cardiac dysfunction. Multi-omics analysis revealed that Fabp3-deficient hearts exhibited disrupted metabolic signatures characterized by increased glycolysis, toxic lipid accumulation, and compromised fatty acid oxidation and ATP production under hypertrophic stimuli. Mechanistically, FABP3 mediated metabolic reprogramming by directly interacting with PPARα, which prevented its degradation and synergistically modulated its transcriptional activity on Mlycd and Gck. Finally, treatment with the PPARα agonist, fenofibrate, rescued the pro-hypertrophic effects of Fabp3 deficiency.Conclusions: Collectively, these findings reveal the indispensable roles of the FABP3–PPARα axis on metabolic homeostasis and the development of hypertrophy, which sheds new light on the treatment of hypertrophy.

Role of metabolic reprogramming toward fatty acid oxidation on tumor lymph node metastasis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14501-e14501
Author(s):  
Choong-kun Lee ◽  
Seung-hwan Jeong ◽  
Cholsoon Jang ◽  
Hosung Bae ◽  
Yoo Hyung Kim ◽  
...  
Keyword(s):  
Lymph Node ◽  
Fatty Acid ◽  
Tumor Cells ◽  
Fatty Acid Oxidation ◽  
Strong Predictor ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Metastatic Tumors ◽  
Genetic Ablation

e14501 Background: Metastasis of tumors to lymph node (LN) is a strong predictor of cancer patient mortality and determinant of disease progression and treatment options. Despite the clinical significance of tumor LN metastasis, the mechanisms underlying this process remain largely unexplored. Methods: We used comparative transcriptomics and metabolomics analyses of the primary tumor and LN micro- and macro-metastatic tumors from B16F10 murine melanoma model. B16F10 melanoma footpad implantation model and MMTV-PyMT spontaneous breast cancer genetic mouse models were analyzed in vivo. We also investigated the LN-metastatic tumors from sentinel LNs in 21 patients with melanoma. Results: We found that tumor cells undergo dramatic metabolic reprogramming towards fatty acid oxidation (FAO) for successful LN metastasis. Mechanistically, transcription co-activator YAP is selectively activated in LN metastatic tumors, leading to stimulation of FAO gene programs. Pharmacological inhibition of FAO or genetic ablation of YAP in tumors markedly suppressed LN metastasis. Unexpectedly, metastatic tumors highly stimulated the bile acid synthesis pathway upon arrival at the LN, and these bile acids activated YAP of tumor cells via nuclear vitamin D receptor. Lastly, YAP activation in the metastatic LNs of melanoma patients was reversely correlated with distant metastasis–free survival. Conclusions: This study propose that inhibition of FAO or YAP signaling to prevent the metabolic reprogramming of metastatic tumors offers a potential therapeutic strategy for mitigating tumor LN metastasis.

scholarly journals Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis

2017 ◽  
Vol 313 (5) ◽  
pp. L834-L844 ◽  
Author(s):  
Na Xie ◽  
Huachun Cui ◽  
Jing Ge ◽  
Sami Banerjee ◽  
Sijia Guo ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Pulmonary Fibrosis ◽  
Fatty Acid Oxidation ◽  
Expression Profile ◽  
Alveolar Macrophages ◽  
Lung Fibrosis ◽  
Metabolic Reprogramming ◽  
Acid Oxidation ◽  
Rna Profiling ◽  
Enhanced Expression

Metabolic reprogramming has been intrinsically linked to macrophage activation. Alveolar macrophages are known to play an important role in the pathogenesis of pulmonary fibrosis. However, systematic characterization of expression profile in these cells is still lacking. Furthermore, main metabolic programs and their regulation of cellular phenotype are completely unknown. In this study, we comprehensively analyzed the expression profile and main metabolic programs in alveolar macrophages from mice with or without experimental pulmonary fibrosis. We found that alveolar macrophages from both bleomycin and active TGF-β1-induced fibrotic mouse lungs demonstrated a primarily profibrotic M2-like profile that was distinct from the well-defined M1 or any of the M2 subtypes. More importantly, we found that fibrotic lung alveolar macrophages assumed augmented glycolysis, which was likely attributed to enhanced expression of multiple key glycolytic mediators. We also found that fatty acid oxidation was upregulated in these cells. However, the profibrotic M2-like profile of fibrotic lung alveolar macrophages was not dependent on fatty acid oxidation and synthesis or lipolysis, but instead on glycolysis, in contrast to the typical IL-4-induced macrophages M(IL-4). Additionally, glutaminolysis, a key metabolic program that has been implicated in numerous pathologies, was not required for the profibrotic M2-like phenotype of these macrophages. In summary, our study identifies a unique expression and metabolic profile in alveolar macrophages from fibrotic lungs and suggests glycolytic inhibition as an effective antifibrotic strategy in treating lung fibrosis.

scholarly journals Metabolic re-patterning in COPD airway smooth muscle cells

2017 ◽  
Vol 50 (5) ◽  
pp. 1700202 ◽  
Author(s):  
Charalambos Michaeloudes ◽  
Chih-Hsi Kuo ◽  
Gulam Haji ◽  
Donna K. Finch ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Airway Smooth Muscle ◽  
Redox Balance ◽  
Growth Conditions ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Acid Oxidation ◽  
Oxidation Capacity

Chronic obstructive pulmonary disease (COPD) airways are characterised by thickening of airway smooth muscle, partly due to airway smooth muscle cell (ASMC) hyperplasia. Metabolic reprogramming involving increased glycolysis and glutamine catabolism supports the biosynthetic and redox balance required for cellular growth. We examined whether COPD ASMCs show a distinct metabolic phenotype that may contribute to increased growth.We performed an exploratory intracellular metabolic profile analysis of ASMCs from healthy nonsmokers, healthy smokers and COPD patients, under unstimulated or growth conditions of transforming growth factor (TGF)-β and fetal bovine serum (FBS).COPD ASMCs showed impaired energy balance and accumulation of the glycolytic product lactate, glutamine, fatty acids and amino acids compared to controls in unstimulated and growth conditions. Fatty acid oxidation capacity was reduced under unstimulated conditions. TGF-β/FBS-stimulated COPD ASMCs showed restoration of fatty acid oxidation capacity, upregulation of the pentose phosphate pathway product ribose-5-phosphate and of nucleotide biosynthesis intermediates, and increased levels of the glutamine catabolite glutamate. In addition, TGF-β/FBS-stimulated COPD ASMCs showed a higher reduced-to-oxidised glutathione ratio and lower mitochondrial oxidant levels. Inhibition of glycolysis and glutamine depletion attenuated TGF-β/FBS-stimulated growth of COPD ASMCs.Changes in glycolysis, glutamine and fatty acid metabolism may lead to increased biosynthesis and redox balance, supporting COPD ASMC growth.

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