Alteration of Serum Free Fatty Acids are Indicators for Progression of Pre-leukaemia Diseases to Leukaemia

Khalid, Ayesha; Siddiqui, Amna Jabbar; Huang, Jianhua; Shamsi, Tahir; Musharraf, Syed Ghulam

doi:10.1038/s41598-018-33224-1

Cited by 19 publications

(19 citation statements)

References 48 publications

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“…Lipid metabolism is a wide and intertwined network that mediates multiple functions, such as energy production [1], thermoregulation [2] and the synthesis of signaling molecules [3], while studies have demonstrated that abnormal levels of lipids contribute to numerous pathologies such as cardiovascular diseases, metabolic diseases and cancer [4]. Fatty acid imbalances have a prognostic value, as their levels in serum can act as tumor biomarkers, or they can predict responses to therapy in multiple cancer types, including leukemia [5], non-small cell lung cancer [6,7], breast cancer [8] and colorectal cancer [9,10].…”

Section: Introductionmentioning

confidence: 99%

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

Sebastiano

Konstantinidou

2019

IJMS

102

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The deregulation of cancer cell metabolic networks is now recognized as one of the hallmarks of cancer. Abnormal lipid synthesis and extracellular lipid uptake are advantageous modifications fueling the needs of uncontrolled cancer cell proliferation. Fatty acids are placed at the crossroads of anabolic and catabolic pathways, as they are implicated in the synthesis of phospholipids and triacylglycerols, or they can undergo β-oxidation. Key players to these decisions are the long-chain acyl-CoA synthetases, which are enzymes that catalyze the activation of long-chain fatty acids of 12–22 carbons. Importantly, the long-chain acyl-CoA synthetases are deregulated in many types of tumors, providing a rationale for anti-tumor therapeutic opportunities. The purpose of this review is to summarize the last up-to-date findings regarding their role in cancer, and to discuss the related emerging tumor targeting opportunities.

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Section: Introductionmentioning

confidence: 99%

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

Sebastiano

Konstantinidou

2019

IJMS

102

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“…Of note, as the only FA significantly different between the stages, C14:0 was overexpressed in stage III-IV compared to stage 0-I, suggesting an association with melanoma progression. High serum levels of free C14:0 were also identified as an indicator for systematic progression of pre-leukemic conditions towards acute myeloid leukemia [77]. Moreover, C14:0 increase was related to risk of breast cancer occurrence in a nested case-control study [78].…”

Section: Discussionmentioning

confidence: 99%

The Fatty Acid and Protein Profiles of Circulating CD81-Positive Small Extracellular Vesicles Are Associated with Disease Stage in Melanoma Patients

Paolino

Huber

Camerini³

et al. 2021

Cancers

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The early detection of cutaneous melanoma, a potentially lethal cancer with rising incidence, is fundamental to increasing survival and therapeutic adjustment. In stages II–IV especially, additional indications for adjuvant therapy purposes after resection and for treatment of metastatic patients are urgently needed. We investigated whether the fatty acid (FA) and protein compositions of small extracellular vesicles (sEV) derived from the plasma of stage 0–I, II and III–IV melanoma patients (n = 38) could reflect disease stage. The subpopulation of sEV expressing CD81 EV marker (CD81sEV) was captured by an ad hoc immune affinity technique from plasma depleted of large EV. Biological macromolecules were investigated by gas chromatography and mass spectrometry in CD81sEV. A higher content of FA was detectable in patients with respect to healthy donors (HD). Moreover, a higher C18:0/C18:1 ratio, as a marker of cell membrane fluidity, distinguished early (stage 0–I) from late (III–IV) stages’ CD81sEV. Proteomics detected increases in CD14, PON1, PON3 and APOA5 exclusively in stage II CD81sEV, and RAP1B was decreased in stage III–IV CD81sEV, in comparison to HD. Our results suggest that stage dependent alterations in CD81sEV’ FA and protein composition may occur early after disease onset, strengthening the potential of circulating sEV as a source of discriminatory information for early diagnosis, prediction of metastatic behavior and following up of melanoma patients.

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“…Membrane biomass is generated by phospholipid biosynthesis that uses fatty acids as building blocks, with FA pools replenished by some combination of triglyceride catabolism, transporter-mediated uptake, and de novo synthesis via the ACLY/ACACA/FASN palmitate production pathway using citrate precursor diverted from the TCA cycle. Indeed, the role of lipid metabolism in AML progression is indicated by changes in serum lipid content 62 , in particular for long-chain saturated fatty acids that are the terminal product of the FAS pipeline. Inhibition of FA synthesis is therefore an appealing chemotherapeutic intervention 63,64 and FASN inhibitors are currently undergoing clinical trials for treatment of solid tumors and metabolic diseases 40 .…”

Section: Variation In Fatty Acid Metabolism In Aml Cellsmentioning

confidence: 99%

Discovery of novel putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in AML cells

Lenoir

Morgado

DeWeirdt

et al. 2020

Preprint

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CRISPR knockout screens in hundreds of cancer cell lines have revealed a substantial number of context-specific essential genes that, when associated with a biomarker such as lineage or oncogenic mutation, offer candidate tumor-specific vulnerabilities for targeted therapies or novel drug development. Data-driven analysis of knockout fitness screens also yields many other functionally coherent modules that show emergent essentiality or, in some cases, the opposite phenotype of faster proliferation. We develop a systematic approach to classify these suppressors of proliferation, which are highly enriched for tumor suppressor genes, and define a network of 103 genes in 22 discrete modules. One surprising module contains several elements of the glycerolipid biosynthesis pathway and operates exclusively in a subset of AML lines, which we call Fatty Acid Synthesis/Tumor Suppressor (FASTS) cells. Genetic and biochemical validation indicates that these cells operate at the limit of their carrying capacity for saturated fatty acids. Overexpression of saturated acyltransferase GPAT4 or its regulator CHP1 confers a survival advantage in an age-matched cohort of AML patients, indicating the in vitro phenotype reflects a clinically relevant subtype, and suggesting a previously unrecognized risk in clinical trials for fatty acid synthesis pathway inhibitors.

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Alteration of Serum Free Fatty Acids are Indicators for Progression of Pre-leukaemia Diseases to Leukaemia

Cited by 19 publications

References 48 publications

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

Targeting Long Chain Acyl-CoA Synthetases for Cancer Therapy

The Fatty Acid and Protein Profiles of Circulating CD81-Positive Small Extracellular Vesicles Are Associated with Disease Stage in Melanoma Patients

Discovery of novel putative tumor suppressors from CRISPR screens reveals rewired lipid metabolism in AML cells

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