Adipocytes Provide Fatty Acids to Acute Lymphoblastic Leukemia Cells

Frontiers in Oncology

Etan Orgel¹  Cheng-Chih Hsu²  Richard N. Zare³  Sarah E. Noll³  Ajit S. Divakaruni⁴  Anthony E. Jones⁴  Matthew J. Oberley⁵  Xia Sheng⁶  Jonathan Tucci⁶  Rachel Wahhab⁶  Steven D. Mittelman⁷  Rebecca L. Paszkiewicz⁷  Michael D. Cohen⁷  Ting Chen⁷  Katherine Margulis⁸ 

[1] Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, Los Angeles, CA, United States;Department of Chemistry, National Taiwan University, Taipei, Taiwan;Department of Chemistry, Stanford University, Stanford, CA, United States;Department of Molecular and Medical Pharmacology, UCLA David Geffen School of Medicine, Los Angeles, CA, United States;Department of Pathology, Children’s Hospital Los Angeles, Los Angeles, CA, United States;Diabetes and Obesity Program, Center for Endocrinology, Diabetes and Metabolism, Children’s Hospital Los Angeles, Los Angeles, CA, United States;Division of Pediatric Endocrinology, University of California Los Angeles (UCLA) Children’s Discovery and Innovation Institute, David Geffen School of Medicine UCLA, Los Angeles, CA, United States;The Institute for Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel;

关键词: adipocytes;    FFA;    microenvironment;    leukemia;    lipid droplets;   

DOI  :  10.3389/fonc.2021.665763

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown