Rewired Metabolism in Drug-resistant Leukemia Cells

Stäubert, Claudia; Bhuiyan, Hasanuzzaman; Lindahl, Anna; Broom, Oliver; Zhu, Yong; Islam, Saiful; Linnarsson, Sten; Lehtiö, Janne; Nordström, Anders

doi:10.1074/jbc.m114.618769

Cited by 66 publications

(53 citation statements)

References 45 publications

(47 reference statements)

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“…Studies showed that carnitine and ALCAR levels are associated with type 2 diabetes and insulin resistance, suggesting that FAO plays a role in the pathogenesis of diabetes [24,25]. Claudia et al reported that drug-resistant human T-lymphoblastic leukemia (CEM) cells exhibited reduced levels of short-chain acyl carnitines, implying a reduction in the FAO rate [26]. Here, we found decreased levels of l-carnitine and ALCAR in BM cells of mice exposed to benzene.…”

Section: Discussionmentioning

confidence: 99%

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Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice

Sun

Cao

Zhang

et al. 2016

IJERPH

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Abstract:Benzene is a well-known hematotoxic carcinogen that can cause leukemia and a variety of blood disorders. Our previous study indicated that benzene disturbs levels of metabolites in the fatty acid β-oxidation (FAO) pathway, which is crucial for the maintenance and function of hematopoietic and leukemic cells. The present research aims to investigate the effects of benzene on changes in the expression of key enzymes in the FAO pathway in male C3H/He mice. Results showed that benzene exposure caused reduced peripheral white blood cell (WBC), red blood cell (RBC), platelet (Pit) counts, and hemoglobin (Hgb) concentration. Investigation of the effects of benzene on the expression of FA transport-and β-oxidation-related enzymes showed that expression of proteins Cpt1a, Crat, Acaa2, Aldh1l2, Acadvl, Crot, Echs1, and Hadha was significantly increased. The ATP levels and mitochondrial membrane potential decreased in mice exposed to benzene. Meanwhile, reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ), and malondialdehyde (MDA) levels were significantly increased in the benzene group. Our results indicate that benzene induces increased expression of FA transport and β-oxidation enzymes, mitochondrial dysfunction, and oxidative stress, which may play a role in benzene-induced hematotoxicity.

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Section: Discussionmentioning

confidence: 99%

“…Acaa2 was reported to be differentially expressed in CEM and drug-resistant leukemia cells [26]. Crot expression was found to be over-expressed in multidrug-resistant K562 leukemia cells [28].…”

Section: Discussionmentioning

confidence: 99%

Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice

Sun

Cao

Zhang

et al. 2016

IJERPH

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“…The linear gradient was 0 min, 5% B; 7 min, 95% B; 9 min, 95% B; 9.2 min, 5% B; 11 min, 5% B. MS data was collected in centroid mode between m/z 70-1700 using the following ESI settings: Gas Temp, 300; Gas Flow, 8; Nebulizer Pressure, 40; Sheet Gas Temp, 350; Sheet Gas Flow, 11; Vcap, 4000; Fragmentor, 100; Skimmer1, 45; OctapoleRFPeak, 750. The analysis procedure has also been described previously (Staubert et al 2015; Lindahl et al 2016). …”

Section: Methodsmentioning

confidence: 99%

Discrimination of pancreatic cancer and pancreatitis by LC-MS metabolomics

et al. 2017

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IntroductionPancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancer-related death in Europe with a 5-year survival rate of <5%. Chronic pancreatitis (CP) is a risk factor for PDAC development, but in the majority of cases malignancy is discovered too late for curative treatment. There is at present no reliable diagnostic marker for PDAC available.ObjectivesThe aim of the study was to identify single blood-based metabolites or a panel of metabolites discriminating PDAC and CP using liquid chromatography-mass spectrometry (LC-MS).MethodsA discovery cohort comprising PDAC (n = 44) and CP (n = 23) samples was analyzed by LC-MS followed by univariate (Student’s t test) and multivariate (orthogonal partial least squares-discriminant analysis (OPLS-DA)) statistics. Discriminative metabolite features were subject to raw data examination and identification to ensure high feature quality. Their discriminatory power was then confirmed in an independent validation cohort including PDAC (n = 20) and CP (n = 31) samples.ResultsGlycocholic acid, N-palmitoyl glutamic acid and hexanoylcarnitine were identified as single markers discriminating PDAC and CP by univariate analysis. OPLS-DA resulted in a panel of five metabolites including the aforementioned three metabolites as well as phenylacetylglutamine (PAGN) and chenodeoxyglycocholate.ConclusionUsing LC-MS-based metabolomics we identified three single metabolites and a five-metabolite panel discriminating PDAC and CP in two independent cohorts. Although further study is needed in larger cohorts, the metabolites identified are potentially of use in PDAC diagnostics.Electronic supplementary materialThe online version of this article (doi:10.1007/s11306-017-1199-6) contains supplementary material, which is available to authorized users.

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“…As previously mentioned, CPT1α protein and mRNA levels both increase in alloreactive T cells during GVHD, and inhibition of CPT1α by etomoxir reduces alloreactive T cell proliferation and decreases disease severity [49]. Interestingly, inhibition of CPT1α by the small molecule ST1326 also decreases fatty acid oxidation and increases apoptosis in both leukemia cell lines and primary leukemia samples [104] and perhexiline, a CPT1α inhibitor approved for use in Australia [105], has shown anti-leukemia effects [106, 107]. The difficulty with many of these compounds is their serious side effect profiles [108], which for etomoxir includes cardiac hypertrophy and for perhexiline involves both neuro- and hepatotoxicity [109, 110].…”

Section: Therapeutic Targeting Of Metabolic Pathwaysmentioning

confidence: 99%

Targeting immuno-metabolism to improve anti-cancer therapies

Beezhold

Byersdorfer

2018

Cancer Letters

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The immunology community has made significant strides in recent years in using the immune system to target and eliminate cancer. Therapies such as hematopoietic stem cell transplantation (HSCT) are the standard of care treatment for several malignancies, while therapies incorporating chimeric antigen receptor (CAR) T cells or checkpoint molecule blockade have been revolutionary. However, these approaches are not optimal for all cancers and in some cases, have failed outright. The greatest obstacle to making these therapies more effective may be rooted in one of the most basic concepts of cell biology, metabolism. Research over the last decade has revealed that T cell proliferation and differentiation is intimately linked to robust changes in metabolic activity, delineation of which may provide ways to manipulate the immuno-oncologic responses to our advantage. Here, we provide a basic overview of T cell metabolism, discuss what is known about metabolic regulation of T cells during allogeneic HSCT, point to evidence on the importance of T cell metabolism during CAR T cell and solid tumor therapies, and speculate about the role for compounds that might have dual-action on both immune cells and tumor cells simultaneously.

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Rewired Metabolism in Drug-resistant Leukemia Cells

Cited by 66 publications

References 45 publications

Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice

Benzene Exposure Alters Expression of Enzymes Involved in Fatty Acid β-Oxidation in Male C3H/He Mice

Discrimination of pancreatic cancer and pancreatitis by LC-MS metabolomics

Targeting immuno-metabolism to improve anti-cancer therapies

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