title: Leptin reverts pro-apoptotic and antiproliferative effects of α-linolenic acids in BCR-ABL positive leukemic cells: involvement of PI3K pathway.
abstract: It is suspected that bone marrow (BM) microenvironmental factors may influence the evolution of chronic myeloid leukaemia (CML). In this study, we postulated that adipocytes and lipids could be involved in the progression of CML. To test this hypothesis, adipocytes were co-cultured with two BCR-ABL positive cell lines (PCMDS and K562). T cell (Jurkat) and stroma cell (HS-5) lines were used as controls. In the second set of experiments, leukemic cell lines were treated with stearic, oleic, linoleic or α-linolenic acids in presence or absence of leptin. Survival, proliferation, leptin production, OB-R isoforms (OB-Ra and OB-Rb), phosphoinositide 3-kinase (PI3k) and BCL-2 expression have been tested after 24h, 48h and 72h of treatment. Our results showed that adipocytes induced a decrease of CML proliferation and an increase in lipid accumulation in leukemic cells. In addition, CML cell lines induced adipocytes cell death. Chromatography analysis showed that BM microenvironment cells were full of saturated (SFA) and monounsaturated (MUFA) fatty acids, fatty acids that protect tumor cells against external agents. Stearic acid increased Bcl-2 expression in PCMDS, whereas oleic and linoleic acids had no effects. In contrast, α-linolenic acid decreased the proliferation and the survival of CML cell lines as well as BCL-2 and OB-R expression. The effect of α-linolenic acids seemed to be due to PI3K pathway and Bcl-2 inhibition. Leptin production was detected in the co-culture medium. In the presence of leptin, the effect of α-linolenic acid on proliferation, survival, OB-R and BCl-2 expression was reduced.
authors: Department of Cytology, Histology and Pathological Anatomy (Giga-R), University of Liege, Liège, Belgium. abeaulieu@ulg.ac.be
authors: Aurore
authors: A
authors: Beaulieu
authors: Géraldine
authors: G
authors: Poncin
authors: Zakia
authors: Z
authors: Belaid-Choucair
authors: Chantal
authors: C
authors: Humblet
authors: Gordana
authors: G
authors: Bogdanovic
authors: Georges
authors: G
authors: Lognay
authors: Jacques
authors: J
authors: Boniver
authors: Marie-Paule
authors: MP
authors: Defresne
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003470:Culture Media / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000096:biosynthesis / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000473:pathology*; D050356:Lipid Metabolism / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017962:alpha-Linolenic Acid / Q000494:pharmacology*
chemical_list: D003470:Culture Media; D020738:Leptin; D019253:Proto-Oncogene Proteins c-bcl-2; D054411:Receptors, Leptin; D017962:alpha-Linolenic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases