Lysophosphatidic Acid Protects Cancer Cells from Histone Deacetylase (HDAC) Inhibitor-induced Apoptosis through Activation of HDAC

Ishdorj, Ganchimeg; Graham, Bonnie A.; Hu, Xiaojie; Chen, Jing; Johnston, James B.; Fang, Xianjun; Gibson, Spencer B.

doi:10.1074/jbc.m710177200

Cited by 31 publications

(26 citation statements)

References 48 publications

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“…The LPA plaque apoptosis was not altered upon LPA challenge, despite the preferential secretion of tryptase, previously shown by us and others ( 6,33 ) as main culprit in mast cellassociated apoptosis. Possibly the pro-apoptotic effects of the mast cell secretome are counteracted by the intrinsic histone deacetylase and serine threonine kinase (Akt)-dependent anti-apoptotic effects of LPA itself ( 27,34 ). However, in our in vitro studies LPA was not able to rescue macrophages from tryptase induced apoptosis, rendering this theory unlikely.…”

Section: Local Lpa Treatment and Plaque Morphologycontrasting

confidence: 51%

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

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Jager

MacAleese

et al. 2013

Journal of Lipid Research

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Atherosclerotic plaque rupture is a leading cause of acute coronary syndromes, such as unstable angina and myocardial infarction ( 1 ). Infl ammatory cells are regarded as key players in the pathogenesis of plaque rupture ( 2, 3 ), and the mast cell, a potent infl ammatory cell, has been shown to accumulate in the rupture-prone shoulder region of human atheromas ( 4 ). Activated mast cells have been identifi ed in the adventitia of vulnerable and ruptured lesions in patients with myocardial infarction, and more importantly, their numbers and degree of activation were found to correlate with the incidence of plaque rupture and erosion ( 5 ). We previously demonstrated that systemic mast cell activation during atherogenesis leads to increased plaque progression in apoE defi cient mice ( 6 ), while others show that the absence of mast cells, and in particular mast cell-derived interleukin (IL)-6 and interferon (IFN)-␥ , attenuated atherosclerotic lesion development in low-density lipoprotein receptor-deficient (LDLr Ϫ / Ϫ ) mice ( 7 ). Moreover, focal activation of mast cells in the adventitia of advanced carotid artery plaques promoted macrophage apoptosis, microvascular leakage, de novo leukocyte infl ux, and the incidence of intraplaque hemorrhage. Mast cell stabilization by cromolyn was seen to prevent these pathophysiological events ( 6 ).Various pathways of mast cell activation have been demonstrated such as cross-linking of the high-affi nity Abstract Lysophosphatidic acid (LPA), a bioactive lysophospholipid, accumulates in the atherosclerotic plaque. It has the capacity to activate mast cells, which potentially exacerbates plaque progression. In this study, we thus aimed to investigate whether LPA contributes to plaque destabilization by modulating mast cell function. We here show by an imaging mass spectrometry approach that several LPA species are present in atherosclerotic plaques. Subsequently, we demonstrate that LPA is a potent mast cell activator which, unlike other triggers, favors release of tryptase. Local perivascular administration of LPA to an atherosclerotic carotid artery segment increases the activation status of perivascular mast cells and promotes intraplaque hemorrhage and macrophage recruitment without impacting plaque cell apoptosis. The mast cell stabilizer cromolyn could prevent intraplaque hemorrhage elicited by LPAmediated mast cell activation. Finally, the involvement of mast cells in these events was further emphasized by the lack of effect of perivascular LPA administration in mast cell defi cient animals. We demonstrate that increased accumulation of LPA in plaques induces perivascular mast cell activation and in this way contributes to plaque destabilization in vivo. This study points to local LPA availability as an important factor in atherosclerotic plaque stability. Press, February 10, 2013 DOI 10.1194 Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular infl ammation Abbreviations: apoE Ϫ / Ϫ , apolipoprotein E-defi...

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Section: Local Lpa Treatment and Plaque Morphologycontrasting

confidence: 51%

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

Bot

Jager

MacAleese

et al. 2013

Journal of Lipid Research

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“…SIRT1 activity was assayed in nuclear fractions isolated from mouse liver and HepG2 cells using a two-step fluorometric technique based on deacetylation of the substrate BocLys(Ac)-7-amino-4-methylcoumarin (Boc-Lys(Ac)-AMC; Bachem, St Helens, UK), followed by trypsin treatment AMC (Ishdorj et al 2008). Nuclear protein isolation was carried out following published methods (Kain et al 2000).…”

Section: Sirt1 Activitymentioning

confidence: 99%

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Caton¹,

Nayuni²,

Kieswich³

et al. 2010

Journal of Endocrinology

176

135

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Abnormal elevation of hepatic gluconeogenesis is central to the onset of hyperglycaemia in patients with type 2 diabetes mellitus (T2DM). Metformin corrects hyperglycaemia through inhibition of gluconeogenesis, but its mechanism of action is yet to be fully described. SIRT1 and GCN5 (listed as KAT2A in the MGI Database) have recently been identified as regulators of gluconeogenic gene expression through modulation of levels and activity of the coactivators cAMP-response element binding protein-regulated transcription coactivator 2 (TORC2 or CRTC2 as listed in the MGI Database) and peroxisome proliferator-activated receptor-g coactivator-1a (PGC1a or PPARGC1A as listed in the MGI Database). We report that in db/db mice, metformin (250 mg/kg per day; 7 days) increases hepatic levels of GCN5 protein and mRNA compared with the untreated db/db mice, as well as increases levels of SIRT1 protein and activity relative to controls and untreated db/db mice. These changes were associated with reduced TORC2 protein level and decreased gene expression and activation of the PGC1a gene target phosphoenolpyruvate carboxykinase, and lower plasma glucose and insulin. Inhibition of SIRT1 partially blocked the effects of metformin on gluconeogenesis. SIRT1 was increased through an AMP-activated protein kinase-mediated increase in gene expression of nicotinamide phosphoribosyltransferase, the rate-limiting enzyme of the salvage pathway for NAD C . Moreover, levels of GCN5 were dramatically reduced in db/db mice compared with the controls. This indicates that loss of GCN5-mediated inhibition of gluconeogenesis appears to constitute a major mechanism for the onset of abnormally elevated hepatic glucose production in db/db mice. In conclusion, induction of GCN5 and SIRT1 potentially represents a critical mechanism of action of metformin. In addition, these data identify induction of hepatic GCN5 as a potential therapeutic strategy for treatment of T2DM.

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“…All cell lines were grown in RPMI 1640 medium (HyCloneThermoScientific) containing 10% fetal calf serum (HyClone ThermoScientific) in a humidified atmosphere (37 C; 5% CO 2 ). Primary B-CLL cells were isolated from patients and maintained as previously described (12). The use of primary CLL cells for this project was approved by the Research Ethics Board at the University of Manitoba.…”

Section: Cellsmentioning

confidence: 99%

“…Lysates were prepared from BJAB, I-83, NALM-6, and primary CLL cells, stimulated with JSI-124, immunoprecipitated with STAT3/1 antibodies, and immunobloted for the expression of STAT3/1 proteins as previously described (12), with antibodies to p-STAT3 ser-727/tyr-705, p-STAT1 (serine 727) or STAT3/1. Immunoblotting was carried out with appropriate antibodies for the expression of Mcl-1, XIAP, caspase 3/8, and cdc2 proteins.…”

Section: Immunoprecipitation and Immunoblot Analysismentioning

confidence: 99%

Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis

Ishdorj

Johnston

Gibson

2010

Molecular Cancer Therapeutics

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Phosphorylation of STAT3 on serine 727 regulates gene expression and is found to be elevated in many Bleukemia cells including chronic lymphocytic leukemia (CLL). It is, however, unclear whether targeting STAT3 will be an effective antileukemia therapy. In this study, we assessed in vitro antileukemia activity of the STAT3 inhibitor JSI-124 (cucurbitacin I). JSI-124 potently induces apoptosis in 3 B-leukemia cell lines (BJAB, I-83, and NALM-6) and in primary CLL cells and was associated with a reduction in serine 727 phosphorylation of STAT3. Similarly, knockdown of STAT3 expression induced apoptosis in these leukemia cells. In addition, we found that JSI-124 and knockdown of STAT3 decreased antiapoptotic protein XIAP expression and overexpression of XIAP blocked JSI-124-induced apoptosis. Furthermore, we found that combined treatment of JSI-124 and TRAIL increased apoptosis associated with an increase in death receptor 4 expression. Besides apoptosis, we found that JSI-124 also induced cell-cycle arrest prior to apoptosis in B-leukemia cells. This corresponded with reduced expression of the cell-cycle regulatory gene, cdc-2. Thus, we present here for the first time that JSI-124 induced suppression of serine 727 phosphorylation of STAT3, leading to apoptosis and cell-cycle arrest through alterations in gene transcription in B-leukemia cells.

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Lysophosphatidic Acid Protects Cancer Cells from Histone Deacetylase (HDAC) Inhibitor-induced Apoptosis through Activation of HDAC

Cited by 31 publications

References 48 publications

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation

Metformin suppresses hepatic gluconeogenesis through induction of SIRT1 and GCN5

Inhibition of Constitutive Activation of STAT3 by Curcurbitacin-I (JSI-124) Sensitized Human B-Leukemia Cells to Apoptosis

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