Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells
Journal
Frontiers in Oncology
Journal Volume
11
Date Issued
2021
Author(s)
Tucci J
Chen T
Margulis K
Orgel E
Paszkiewicz R.L
Cohen M.D
Oberley M.J
Wahhab R
Jones A.E
Divakaruni A.S
Noll S.E
Sheng X
Zare R.N
Mittelman S.D.
Abstract
Background: There is increasing evidence that adipocytes play an active role in the cancer microenvironment. We have previously reported that adipocytes interact with acute lymphoblastic leukemia (ALL) cells, contributing to chemotherapy resistance and treatment failure. In the present study, we investigated whether part of this resistance is due to adipocyte provision of lipids to ALL cells. Methods: We cultured 3T3-L1 adipocytes, and tested whether ALL cells or ALL-released cytokines induced FFA release. We investigated whether ALL cells took up these FFA, and using fluorescent tagged BODIPY-FFA and lipidomics, evaluated which lipid moieties were being transferred from adipocytes to ALL. We evaluated the effects of adipocyte-derived lipids on ALL cell metabolism using a Seahorse XF analyzer and expression of enzymes important for lipid metabolism, and tested whether these lipids could protect ALL cells from chemotherapy. Finally, we evaluated a panel of lipid synthesis and metabolism inhibitors to determine which were affected by the presence of adipocytes. Results: Adipocytes release free fatty acids (FFA) when in the presence of ALL cells. These FFA are taken up by the ALL cells and incorporated into triglycerides and phospholipids. Some of these lipids are stored in lipid droplets, which can be utilized in states of fuel deprivation. Adipocytes preferentially release monounsaturated FFA, and this can be attenuated by inhibiting the desaturating enzyme steroyl-CoA decarboxylase-1 (SCD1). Adipocyte-derived FFA can relieve ALL cell endogenous lipogenesis and reverse the cytotoxicity of pharmacological acetyl-CoA carboxylase (ACC) inhibition. Further, adipocytes alter ALL cell metabolism, shifting them from glucose to FFA oxidation. Interestingly, the unsaturated fatty acid, oleic acid, protects ALL cells from modest concentrations of chemotherapy, such as those that might be present in the ALL microenvironment. In addition, targeting lipid synthesis and metabolism can potentially reverse adipocyte protection of ALL cells. Conclusion: These findings uncover a previously unidentified interaction between ALL cells and adipocytes, leading to transfer of FFA for use as a metabolic fuel and macromolecule building block. This interaction may contribute to ALL resistance to chemotherapy, and could potentially be targeted to improve ALL treatment outcome. ? Copyright ? 2021 Tucci, Chen, Margulis, Orgel, Paszkiewicz, Cohen, Oberley, Wahhab, Jones, Divakaruni, Hsu, Noll, Sheng, Zare and Mittelman.
Subjects
adipocytes
FFA
leukemia
lipid droplets
microenvironment
acetyl coenzyme A carboxylase
carboxylyase
citrinin
cytochrome c
daunorubicin
dexamethasone
etomoxir
fat droplet
fatty acid synthase
fenofibrate
gentamicin
glucose transporter 4
glycerol
interleukin 12
interleukin 16
interleukin 6
interleukin 7
ketamine
lactic acid
macrophage inflammatory protein 1alpha
monocyte chemotactic protein 1
monounsaturated fatty acid
oleic acid
palmitic acid
peroxisome proliferator activated receptor gamma
phospholipid
RANTES
sterol regulatory element binding protein 1c
tetrahydrolipstatin
triacylglycerol
unsaturated fatty acid
vincristine
3T3-L1 cell line
acute lymphoblastic leukemia
adipocyte
adipose tissue
adolescent
adult
animal cell
animal tissue
Article
bioenergy
bone marrow biopsy
breathing rate
cancer chemotherapy
cancer resistance
cardiac muscle cell
cell killing
cell metabolism
cell proliferation
cell survival
chemotherapy
child
clinical trial (topic)
coculture
confocal microscopy
controlled study
cytokine release
cytotoxicity
EC50
endoplasmic reticulum stress
fatty acid oxidation
flow cytometry
gene expression
glucose transport
glycolysis
human
human cell
human tissue
IC50
immunoblotting
immunofluorescence
immunofluorescence assay
inflammation
lipid metabolism
lipidomics
lipogenesis
lipolysis
macromolecule
male
mass spectrometry
mitochondrial respiration
mouse
nonhuman
nuclear reprogramming
obesity
oxidative phosphorylation
pentose phosphate cycle
protein expression
protein phosphorylation
respirometry
teratoma
treadmill exercise
treatment failure
young adult
Type
journal article