Leptin Reverts Pro-Apoptotic and Antiproliferative Effects of a-Linolenic Acids in BCR-ABL Positive Leukemic Cells: Involvement of PI3K Pathway

January 1, 2011 Human Health and Nutrition Data 0 Comments

Leptin Reverts Pro-Apoptotic and Antiproliferative Effects of a-Linolenic Acids in BCR-ABL Positive Leukemic Cells: Involvement of PI3K Pathway

Year: 2011
Authors: Beaulieu, A. Poncin, G. Belaid-Choucair, Z. Humblet, C. Bogdanovic, G. Lognay, G. Boniver, J. Defresne, M.-P.
Publication Name: PLoS One
Publication Details: Volume 6; Number 10; Pages e25651 – e25662.

Abstract:

It is suspected that bone marrow (BM) micro environmental 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 a-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, a-linolenic acid decreased the proliferation and the survival of CML cell lines as well as BCL2 and OB-R expression. The effect of a-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 alpha-linolenic acid on proliferation, survival, OB-R and BCl-2 expression was reduced. (Authors abstract)
Chronic myelogenous leukemia (CML) is a malignant disorder of the hematopoietic stem cell (HSC) characterized by a reciprocal translocation between chromosomes 9 and 22. Many mechanisms are involved in the malignant transformation stimulated by the BCR-ABL oncoprotein including the activation of mitogenic signaling pathways such as the phosphoinositide-3 (PI3) kinase pathway. Once activated, the PI3K controls cell growth, proliferation and apoptosis, as well as steps that are involved in tumor formation and malignant cell dissemination. Alterations in bone marrow including altered cytokine production promote a proinflammatory environment. Genes coding for the receptor of leptin (OB-R), an adipokine produced predominantly by adipocytes, and for proteins involved in fatty acid synthesis are upregulated in CML cells. This up regulation was directly associated with activation of the PI3K signaling pathway. Lipid accumulation in the BM associated with OB-R expression and PI3K/AKT signalling activation led the authors to speculate that fat cells and lipids could be involved in the evolution of the disease. In this study, the possible role of adipocytes, leptin and fatty acids in the CML disease progression were assessed by analysing interactions between BM adipocytes and BCR-ABL positive cell lines and exploring the potential effects of leptin and fatty acids on these cell lines. The results showed that adipocytes induced a decrease in BCR-ABL positive cell lines proliferation but did not influence Jurkat cells. By contrast, HS-5 stromal cells did not influence leukemic cells. Chromatographic analyses of the BM aspirates and biopsies of healthy patients showed a clear difference between the lipid composition of supernatant and cells of the BM microenvironment. The supernatant were rich in PUFA, while the cells were full of SFA and MUFA. Stearic acid increased the Bcl-2 expression, whereas others fatty acids (oleic and linoleic acids) had no effects. In contrast, alpha-linolenic acid decreased BCL-2 and OB-R expression in CML cell lines and reduced the proliferation and the survival of these cell lines. In the presence of leptin, the effects of alpha-linolenic acid on proliferation, survival, OB-R and BCl-2 were reduced. The results suggest that an adipocyte-rich composition of stearic and oleic acid promotes the development of leukemia, while alpha-linolenic acid exerts an inhibitory effect. Leptin can counteract alpha-linolenic acid inhibitory effects. (Editors comments)



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