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

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 TALL 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. Acute lymphoblastic leukemia (ALL) is the most common type of hematological malignancy in children 1,2. Despite the enormous advances in modern medicine and development of innovative therapeutic strategies, disease relapse remains a leading cause of cancer-related morbidity and mortality in children 3. Metabolic rearrangements are vital to satisfy the different requirements of cancer cells during tumorigenesis 4. Elevated de novo fatty acid biosynthesis is a hallmark adaptation in many cancers that supply signaling molecules and basic elements for lipid biosynthesis 5. While most normal cells supply their fatty acids from dietary sources, cancer cells reactivate de novo fatty acid synthesis 6. Fatty acid synthase (FASN) is a multifunctional protein containing six enzymatic domains that catalyzes the biosynthesis of palmitate 5. Elevated expression of FASN is found to be associated with poor prognosis and higher risk of recurrence in a number of human cancers. Indeed, FASN overexpression has been shown to contribute to multidrug resistance (MDR). Multi-drug resistance is one of the major obstacles to the successful treatment of various types of cancer, particularly childhood ALL 5,7,8. Glucocorticoids (GCs) such as prednisone and dexamethasone (DEX) are indispensable drugs for childhood ALL treatment 9. Early response to glucocorticoids is a positive prognostic indicator and glucocorticoid resistance has been associated with an increased risk of relapse and poor clinical response 10,11. Glucocorticoids regulate FASN expression and subsequently affect lipogenesis 12. Therefore, FASN knock down or...

6‐Shogaol induces apoptosis in acute lymphoblastic leukaemia cells by targeting p53 signalling pathway and generation of reactive oxygen species

“…It was previously declared that ROS may cause DNA damage, contributing to p53 activation followed by apoptosis 34,35 . Interestingly, FASN overexpression is recently introduced by our group as a negative prognostic factor for paediatric ALL 24 . Additionally, the association of FASN with resistance to chemotherapeutic drugs was previously determined 36 .…”

“…Fatty acid synthase (FASN) is another key regulator which may be responsible for leukaemia drug resistance. According to our previous study FASN expression levels are upregulated in ALL drug resistant children, and they may be reduced by cells treating with ginger extract 24 . It would be interesting to know which ginger derivative could play role in the FASN molecular pathway.…”

Characterization of a novel glucocorticoid-resistant human B-cell acute lymphoblastic leukemia cell line, with AMPK, mTOR and fatty acid synthesis pathway inhibition

“…Upon hypoxic stress, different cancer cells had different cell-type-specific regulation of FASN, increased, decreased or unaffected [ 42 ]. A recent paper reported that FASN was upregulated in relapsed ALL patients; moreover, FASN inhibition may help to overcome glucocorticoid resistance [ 43 ]. FASN inhibition may sensitize AML cells to differentiation therapy [ 13 ].…”

Reprogramming lipid metabolism as potential strategy for hematological malignancy therapy

“…Clinically, glucocorticoids such as prednisone and dexamethasone can inhibit the expression of FASN and thereby inhibit the proliferation and growth of tumor cells ( 71 ). At the same time, the study found that ginger extract can inhibit the expression of FASN, and combined use with dexamethasone can enhance the drug sensitivity of ALL cells to dexamethasone ( 72 ). The combination of bezafibrate and medroxyprogesterone acetate ( 39 ), orlistat ( 73 ), N-phenylmaleimide ( 74 ) and methyl jasmonate ( 75 ) can all regulate the expression of FASN to inhibit the growth of tumor cells.…”