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      Low Density Lipoproteins Amplify Cytokine-signaling in Chronic Lymphocytic Leukemia Cells

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          Abstract

          Recent studies suggest there is a high incidence of elevated low-density lipoprotein (LDL) levels in Chronic Lymphocytic Leukemia (CLL) patients and a survival benefit from cholesterol-lowering statin drugs. The mechanisms of these observations and the kinds of patients they apply to are unclear. Using an in vitro model of the pseudofollicles where CLL cells originate, LDLs were found to increase plasma membrane cholesterol, signaling molecules such as tyrosine-phosphorylated STAT3, and activated CLL cell numbers. The signaling effects of LDLs were not seen in normal lymphocytes or glycolytic lymphoma cell-lines but were restored by transduction with the nuclear receptor PPARδ, which mediates metabolic activity in CLL cells. Breakdown of LDLs in lysosomes was required for the amplification effect, which correlated with down-regulation of HMGCR expression and long lymphocyte doubling times (LDTs) of 53.6 ± 10.4 months. Cholesterol content of circulating CLL cells correlated directly with blood LDL levels in a subgroup of patients. These observations suggest LDLs may enhance proliferative responses of CLL cells to inflammatory signals. Prospective clinical trials are needed to confirm the therapeutic potential of lowering LDL concentrations in CLL, particularly in patients with indolent disease in the “watch-and-wait” phase of management.

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          Highlights

          • Slow-growing CLL cells use lysosomal lipase to break low density lipoproteins (LDLs) into free fatty acids and cholesterol.

          • LdL degradation products increase survival of proliferating CLL cells.

          • LDLs decrease oxidative stress and increase plasma membrane cholesterol.

          • LDLs amplify signaling responses to cytokines but not antigens in proliferating CLL cells.

          • Rapidly growing CLL cells, acute leukemia cells, and normal lymphocytes do not exhibit this dependence on LDLs.

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          Most cited references36

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          Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies.

          The physiological importance of cholesterol in the cell plasma membrane has attracted increased attention in recent years. Consequently, the use of methods of controlled manipulation of membrane cholesterol content has also increased sharply, especially as a method of studying putative cholesterol-enriched cell membrane domains (rafts). The most common means of modifying the cholesterol content of cell membranes is the incubation of cells or model membranes with cyclodextrins, a family of compounds, which, due to the presence of relatively hydrophobic cavity, can be used to extract cholesterol from cell membranes. However, the mechanism of this activity of cyclodextrins is not completely established. Moreover, under conditions commonly used for cholesterol extraction, cyclodextrins may remove cholesterol from both raft and non-raft domains of the membrane as well as alter the distribution of cholesterol between plasma and intracellular membranes. In addition, other hydrophobic molecules such as phospholipids may also be extracted from the membranes by cyclodextrins. We review the evidence for the specific and non-specific effects of cyclodextrins and what is known about the mechanisms for cyclodextrin-induced cholesterol and phospholipid extraction. Finally, we discuss useful control strategies that may help to verify that the observed effects are due specifically to cyclodextrin-induced changes in cellular cholesterol.
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            The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B cells.

            Sustained engagement of the B-cell receptor (BCR) increases apoptosis resistance in chronic lymphocytic leukemia (CLL) B cells, whereas transient stimulation usually has an opposite effect. The antiapoptotic BCR signal has been associated with prolonged activation of the PI3K/Akt and MEK/ERK pathways, which are key regulators of survival and proliferation in various cell types. To further define the relative contribution of the Akt and ERK kinases in regulating CLL B-cell survival, we introduced constitutively active mutants of Akt and MEK in primary CLL B cells and evaluated changes in the expression of relevant pro- and antiapoptotic proteins. Sustained activation of Akt resulted in increased leukemic cell viability and increased expression of the antiapoptotic proteins Mcl-1, Bcl-xL, and X-linked inhibitor of apoptosis protein (XIAP), thus largely recapitulating the effects of sustained BCR stimulation. Constitutively active MEK2 also up-regulated XIAP, but did not show a significant impact on leukemic cell survival. Down-regulation of Mcl-1 by siRNA treatment induced rapid and potent apoptosis in CLL B cells and blocked the antiapoptotic effect of sustained BCR stimulation, whereas down-regulation of Bcl-xL and XIAP did not affect leukemic cell viability. These data demonstrate that Akt and Mcl-1 are major components of a survival pathway that can be activated in CLL B cells by antigen stimulation.
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              Impact of the obesity epidemic on cancer.

              There is growing appreciation that the current obesity epidemic is associated with increases in cancer incidence at a population level and may lead to poor cancer outcomes; concurrent decreases in cancer mortality at a population level may represent a paradox, i.e., they may also reflect improvements in the diagnosis and treatment of cancer that mask obesity effects. An association of obesity with cancer is biologically plausible because adipose tissue is biologically active, secreting estrogens, adipokines, and cytokines. In obesity, adipose tissue reprogramming may lead to insulin resistance, with or without diabetes, and it may contribute to cancer growth and progression locally or through systemic effects. Obesity-associated changes impact cancer in a complex fashion, potentially acting directly on cells through pathways, such as the phosphoinositide 3-kinase (PI3K) and Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways, or indirectly via changes in the tumor microenvironment. Approaches to obesity management are discussed, and the potential for pharmacologic interventions that target the obesity-cancer link is addressed.
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                Author and article information

                Contributors
                Journal
                EBioMedicine
                EBioMedicine
                EBioMedicine
                Elsevier
                2352-3964
                30 November 2016
                February 2017
                30 November 2016
                : 15
                : 24-35
                Affiliations
                [a ]Biology Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada
                [b ]Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada
                [c ]Department of Nutritional Sciences, University of Toronto, Toronto, ON, Canada
                [d ]Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada
                [e ]Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 2M9, Canada
                [f ]Sunnybrook Odette Cancer Center, Toronto, ON M4N 3M5, Canada
                [g ]Department of Human Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
                Author notes
                [* ]Corresponding author at.: David Spaner, Biology Platform, S-116A, Research Building, Sunnybrook Research Institute, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada.Biology PlatformSunnybrook Research InstituteS-116A, Research Building2075 Bayview AvenueTorontoONM4N 3M5Canada spanerd@ 123456sri.utoronto.ca
                Article
                S2352-3964(16)30548-5
                10.1016/j.ebiom.2016.11.033
                5233814
                27932296
                12cdac31-6de3-492b-aa61-962ce644156f
                © 2016 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 March 2016
                : 26 November 2016
                : 28 November 2016
                Categories
                Research Paper

                chronic lymphocytic leukemia,janus kinases,stat3,ruxolitinib,cholesterol,lipoproteins,lysosomal lipase,hmgcr,nuclear receptors

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