A reversible carnitine palmitoyltransferase (CPT1) inhibitor offsets the proliferation of chronic lymphocytic leukemia cells

Gugiatti, Elena; Tenca, Claudya; Ravera, Silvia; Fabbi, Marina; Ghiotto, Fabio; Mazzarello, Andrea Nicola; Bagnara, Davide; Reverberi, Daniele; Zarcone, Daniela; Cutrona, Giovanna; Ibatici, Adalberto; Ciccone, Ermanno; Darżynkiewicz, Zbigniew; Fais, Franco; Bruno, Silvia

doi:10.3324/haematol.2017.175414

Cited by 24 publications

(25 citation statements)

References 15 publications

(16 reference statements)

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“…In particular, targeting of FFA oxidation could reverse the advantage that cancer cells have in lipid rich environments. CPT1A inhibitors, such as etomoxir and ST1326, are effective against hematologic malignancies (19)(20)(21)(22), and in our hands, nearby adipocytes actually enhanced the cytotoxicity of etomoxir against ALL (Figure 8). Conversely, the cytotoxicity of half of the fatty acid synthesis inhibitors we tested were reversed by adipocytes.…”

Section: Discussionsupporting

confidence: 51%

“…These results reveal potential strategies that could be directed against environmentally-mediated chemotherapy resistance in ALL. Inhibition of FFA utilization has shown promise against a variety of cancers (16)(17)(18)(19)(20)(21)(22). In particular, targeting of FFA oxidation could reverse the advantage that cancer cells have in lipid rich environments.…”

Section: Discussionmentioning

confidence: 99%

“…Further, which lipids are provided to nearby cancer cells and how these affect metabolism and survival is not fully understood, particularly in ALL. These are important questions, as strategies are being developed to target lipid biosynthesis or metabolism in several cancers (16)(17)(18)(19)(20)(21)(22)(23)(24). Because the bone marrow is an adipocyte-rich environment, these interactions could be particularly relevant to hematologic cancers.…”

Section: Introductionmentioning

confidence: 99%

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Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells

et al. 2021

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BackgroundThere 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.MethodsWe 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.ResultsAdipocytes 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.ConclusionThese 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.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells

et al. 2021

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“…The study was conducted on quiescent leukemic cells and on cells stimulated in vitro by lymphoid tissue-mimicking microenvironment stimuli (CD40L + IL-4 and CpG-ODN2006 + IL-15) 13,14 . CLL samples were derived from patients with heterogeneous clinical and molecular prognostic markers, including patients with aggressive disease (Binet B and C) or with unfavorable prognostic markers (i.e.…”

Section: Resultsmentioning

confidence: 99%

“…Multiparameter flow-cytometric analysis of cellular viability by propidium iodide (PI) exclusion assays, expression of surface (adhesion/homing) and intracellular (KI-67, cyclins and Mcl-1/Bcl-xL) proteins, Annexin V-FITC/PI fluorescence, mitochondrial transmembrane potential (∆Ψ) and cell cycle-phase distribution by DNA content were previously described 13 , 14 .…”

Section: Methodsmentioning

confidence: 99%

Berberine affects mitochondrial activity and cell growth of leukemic cells from chronic lymphocytic leukemia patients

Ravera

Ghiotto

Tenca

et al. 2020

Sci Rep

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B-cell chronic lymphocytic leukemia (CLL) results from accumulation of leukemic cells that are subject to iterative re-activation cycles and clonal expansion in lymphoid tissues. The effects of the well-tolerated alkaloid Berberine (BRB), used for treating metabolic disorders, were studied on ex-vivo leukemic cells activated in vitro by microenvironment stimuli. BRB decreased expression of survival/proliferation-associated molecules (e.g. Mcl-1/Bcl-xL) and inhibited stimulation-induced cell cycle entry, irrespective of TP53 alterations or chromosomal abnormalities. CLL cells rely on oxidative phosphorylation for their bioenergetics, particularly during the activation process. In this context, BRB triggered mitochondrial dysfunction and aberrant cellular energetic metabolism. Decreased ATP production and NADH recycling, associated with mitochondrial uncoupling, were not compensated by increased lactic fermentation. Antioxidant defenses were affected and could not correct the altered intracellular redox homeostasis. The data thus indicated that the cytotoxic/cytostatic action of BRB at 10–30 μM might be mediated, at least in part, by BRB-induced impairment of oxidative phosphorylation and the associated increment of oxidative damage, with consequent inhibition of cell activation and eventual cell death. Bioenergetics and cell survival were instead unaffected in normal B lymphocytes at the same BRB concentrations. Interestingly, BRB lowered the apoptotic threshold of ABT-199/Venetoclax, a promising BH3-mimetic whose cytotoxic activity is counteracted by high Mcl-1/Bcl-xL expression and increased mitochondrial oxidative phosphorylation. Our results indicate that, while CLL cells are in the process of building their survival and cycling armamentarium, the presence of BRB affects this process.

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Lipid metabolism in B cell biology

Peeters,

Jellusova

2023

Molecular Oncology

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In recent years, the field of immunometabolism has solidified its position as a prominent area of investigation within the realm of immunological research. An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signalling molecules, and metabolites in relation to fundamental aspects of our immune cells. It is now widely accepted that disruptions in metabolic equilibrium can give rise to a myriad of pathological conditions, ranging from autoimmune disorders to cancer. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behaviour of immune cells, including B cells. In light of these findings, this review aims to provide a comprehensive overview of the current state of knowledge regarding lipid metabolism in the context of B cell biology.

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A reversible carnitine palmitoyltransferase (CPT1) inhibitor offsets the proliferation of chronic lymphocytic leukemia cells

Cited by 24 publications

References 15 publications

Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells

Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells

Berberine affects mitochondrial activity and cell growth of leukemic cells from chronic lymphocytic leukemia patients

Lipid metabolism in B cell biology

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