Fatty acid synthase, a novel poor prognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract

Maryam Ghaeidamini Harouni,Soheila Rahgozar,Elaheh Sadat Ghodousi,Arman Safavi,Somayeh Rahimi Babasheikhali

doi:10.1038/s41598-020-70839-9

Maryam Ghaeidamini Harouni, Soheila Rahgozar + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-70839-9

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Journal: Scientific Reports	Publication Date: Aug 21, 2020
Citations: 12	License type: open-access

Affiliation: University of Isfahan

Abstract

Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL). To evaluate the impact of fatty acid synthase (FASN) on drug resistant ALL, bone marrow samples were collected from 65 pediatric ALLs, including 40 de novo and 25 relapsed patients. 22 non-cancer individuals were chosen as controls. Quantitative RT-PCR showed increased expression levels of FASN in drug resistant patients compared with the therapy responders. Single and combined treatment of malignant cells were analyzed using Annexin-V/PI double staining and MTT assays. Incubation of resistant primary cells with ginger showed simultaneous increased apoptosis rates and reduced FASN expression levels. Furthermore, docking studies demonstrated high affinity bindings between ginger derivatives and FASN thioesterase and ketosynthase domains, compared with their known inhibitors, fenofibrate and morin, respectively. Finally, combined treatment of in-house multidrug resistant T-ALL subline with ginger and dexamethasone induced drug sensitivity and down regulation of FASN expression, accordingly. To the best of our knowledge, this is the first study that introduces FASN upregulation as a poor prognostic factor for drug resistant childhood ALL. Moreover, it was revealed that FASN inhibition may be applied by ginger phytochemicals and overcome dexamethasone resistance, subsequently.

Highlights

Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL)
No evidence of cancer was found in their bone marrow aspirates. Regarding their response to one year chemotherapy, the newly diagnosed patients were divided into 9 minimal residual disease (MRD)+ and 31 MRD− patients followed by PCR-SSCP analyses
fatty acid synthase (FASN) overexpression has shown to be associated with poor prognosis and resistance to c hemotherapy[20]

Summary

Introduction

Altered metabolism of fatty acid synthesis is considered a hallmark characteristic of several malignancies, including acute lymphoblastic leukemia (ALL). To evaluate the impact of fatty acid synthase (FASN) on drug resistant ALL, bone marrow samples were collected from 65 pediatric ALLs, including 40 de novo and 25 relapsed patients. Quantitative RT-PCR showed increased expression levels of FASN in drug resistant patients compared with the therapy responders. Incubation of resistant primary cells with ginger showed simultaneous increased apoptosis rates and reduced FASN expression levels. Combined treatment of in-house multidrug resistant T-ALL subline with ginger and dexamethasone induced drug sensitivity and down regulation of FASN expression, . Elevated expression of FASN is found to be associated with poor prognosis and higher risk of recurrence in a number of human cancers. Patient characteristics Sex Male Female ALL immunophenotype T cell linage Pre-B and early pre-B linage Cytogenetics T (4;11)/KMT2A-AFF1 T (9;22)/BCR-ABL1 T(1;19)/TCF3-PBX1 T(12;21)/ETV6-RUNX1 MRD− Pre-B cell T cell Total MRD− MRD+ Pre-B cell T cell Total MRD+ Relapse Pre-B cell T cell Total relapse

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