Augmentation of methylprednisolone-induced differentiation of myeloid leukemia cells by serine/threonine protein phosphatase inhibitors

Uzunoğlu, Selim; Uslu, Rüçhan; Töbü, Mahmut; Saydam, Güray; Terzıoğlu, Ender; Büyükkeçeci, Filiz; Omay, Serdar Bedii

doi:10.1016/s0145-2126(99)00040-5

Cited by 24 publications

(13 citation statements)

References 17 publications

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“…The inhibition of the serine/treonine phosphatase PP2A observed after the treatment is in agreement with other work that shows induction of apoptosis by PP2A inhibitors [32]. Moreover, the inhibition of PP2A is correlated to differentiation of HL60 cells [33,34] and indicates that the induction of death may be a result of a terminal differentiation induced by irradiated riboflavin.…”

Section: Discussionsupporting

confidence: 91%

A promising action of riboflavin as a mediator of leukaemia cell death

et al. 2006

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Besides having a pivotal biological function as a component of coenzymes, riboflavin appears a promissing antitumoral agent, but the underlying molecular mechanism remains unclear. In this work, we demonstrate that irradiated riboflavin, when applied at microM concentrations, induces an orderly sequence of signaling events finally leading to leukemia cell death. The molecular mechanism involved is dependent on the activation of caspase 8 caused by overexpression of Fas and FasL and also on mitochondrial amplification mechanisms, involving the stimulation of ceramide production by sphingomyelinase and ceramide synthase. The activation of this cascade led to an inhibition of mitogen activated protein kinases: JNK, MEK and ERK and survival mediators (PKB and IAP1), upregulation of the proapoptotic Bcl2 member Bax and downregulation of cell cycle progression regulators. Importantly, induction of apoptosis by irradiated riboflavin was leukaemia cell specific, as normal human lymphocytes did not respond to the compound with cell death. Our data indicate that riboflavin selectively activates Fas cascade and also constitutes a death receptor-engaged drug without harmful side effects in normal cells, bolstering the case for using this compound as a novel avenue for combating cancerous disease.

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Section: Discussionsupporting

confidence: 91%

A promising action of riboflavin as a mediator of leukaemia cell death

et al. 2006

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“…This result suggested that PP2A was involved in the dephosphorylation process although it did not exclude the possibility of the involvement of other phosphatases such as PP1, PP4 and PP5, which are inhibited by low (in cases of PP2A, PP4, PP6) or high (in case of PP1) concentrations of okadaic acid. [38][39][40] Since the result of time course of HNEinduced Akt dephosphorylation (Figure 2b) corresponded well to the time course of HNE-induced caspase activation in our earlier study, 37 we carried out an experiment to determine whether dephosphorylation of Akt is a consequence of caspase activation. Pretreatment of the cells with a specific …”

Section: Inhibition Of Pp2a or Caspase-3 Prevents Akt Dephosphorylationsupporting

confidence: 62%

“…Our results showing the rescue of HNE-mediated dephosphorylation of Akt by the PP2A inhibitor okadaic acid (Figure 3) led us to assume that PP2A plays a role in the process of this dephosphorylation. Since okadaic acid inhibits not only PP2A but also PP1, PP4 or PP5, [38][39][40] there remains the possibility that multiple phosphatases are involved in the mechanism, although 1,2-dioleoyl-sn-glycero-3-phosphate, an inhibitor of PP1 48 did not obviously inhibit the phosphatase activity on phospho-Akt (Liu et al, unpublished data). The assumption that PP2A plays a key role in the regulation of Akt, whether or not other phosphatases are additionally involved, was, however, supported by the finding of HNE-induced increase in binding of Akt with PP2A (Figure 4), through a relatively low concentration of okadaic acid-sensitive mechanism, that might have favored the enzyme (PP2A)-substrate (Akt) reaction for dephosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal

et al. 2003

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We studied the signal pathways for regulation of serine/ threonine protein kinase Akt in Jurkat cells that had been treated with 4-hydroxynonenal (HNE) for caspase-dependent apoptosis induction. Treatment of cells with HNE led to a decrease in the level of Akt activity due to the dephosphorylation at Ser473, a major regulatory phosphorylation site. HNE-mediated dephosphorylation of Akt was prevented by a protein phosphatase 2A (PP2A) inhibitor, okadaic acid, and by a caspase-3 inhibitor, DEVD-CHO. HNE treatment resulted in an increase in the total level of PP2A activity, release of active tyrosine-dephosphorylated PP2A from the cytoskeleton and PP2A-Akt association, which were all dependent on caspase-3 activation. These results suggest that the level of PP2A activity is at least in part determined by its tyrosine phosphorylation, which is dually controlled by okadaic acid-sensitive phosphatases and protein-tyrosine kinases. Possibly underlying the mechanism of caspase-mediated activation of PP2A, HNE treatment resulted in downregulation of the activity of Src kinase, as a representative caspase-sensitive kinase to phosphorylate PP2A at tyrosine. In addition, activated caspase-3 partially cleaved Akt at a late stage of the apoptosis. These results indicate the existence of two distinct caspasedependent signal pathways for downregulation of Akt that works as a mechanism of positive feedback regulation for HNEtriggered apoptotic signals.

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“…This cell line is generally accepted as a valid model for studying myeloid leukemia biology. 7,8 Melo et al 6 showed earlier that HL60 cells react to violacein with both increased cell death and diminished cellular proliferation. Hence, this cell type is attractive for studying the molecular mechanism of violacein, and we compared its effects to those observed in peripheral lymphocytes and monocytes of healthy donors and to its effects in cell types representing other types of leukemia.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of violacein-mediated human leukemia cell death

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Bos

Versteeg

et al. 2004

Blood

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Violacein, a pigment isolated from Chromobacterium violaceum in the Amazon River, presents diverse biologic properties and attracts interest as a consequence of its antileukemic activity. Elucidation of the molecular mechanism mediating this activity will provide further relevant information for understanding its effects on the cellular physiology of untransformed cells and for considering its possible clinical application. Here, we show that violacein causes apoptosis in HL60 leukemic cells but is ineffective in this respect in other types of leukemia cells or in normal human lymphocytes and monocytes. Violacein cytotoxicity in HL60 cells was preceded by activation of caspase 8, transcription of nuclear factor B (NF-B) target genes, and p38 mitogenactivated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor ␣ (TNF-␣) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-␣-induced signaling abolished the biologic activity of violacein. Moreover, violacein directly activated TNF receptor 1 signaling, because a violacein-dependent association of TNF receptor-associated factor 2 (TRAF2) to this TNF receptor was observed in coimmunoprecipitation experiments. Hence, violacein represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of TNF receptor 1. IntroductionViolacein ( Figure 1A), a purple-colored pigment produced by one of the strains of Chromobacterium violaceum found in the Amazon River, Brazil, is an indole derivative characterized as 3-(1,2-dihydro-5-(5-hydroxy-1H-indol-3-yl)-2-oxo-3H-pyrrol-3-ilydene)-1,3-dihydro-2H-indol-2-one. 1 The biosynthesis and biologic properties of this pigment have been extensively studied; in particular, its antitumoral, antibacterial, antiulcerogenic, antileishmanial, and antiviral activities are of interest. [1][2][3][4][5][6] Its activity on acute myeloblastic leukemia (HL60) cells is of special interest because the compound effectively induces cell death in these cells.The development of violacein as a possible novel therapeutic avenue for the treatment of leukemia, however, depends on the establishment of the molecular basis for this cytotoxicity. Evidently, a possible future application of violacein as a therapeutic agent critically depends on its ability to target leukemia cells more effectively than normal blood cells. Hence, research comparing the cytotoxicity of violacein in transformed cells and the corresponding untransformed ones is urgently called for. In addition, identification of the molecular details mediating violacein effects on leukemic cells will provide insight into the possible benefit of this compound in comparison to existing therapeutics.The above-mentioned considerations prompted us to investigate the effects of violacein in HL60 cells. This cell line is generally accepted as a valid model for studying myeloid leukemia biology. 7,8 Melo et al 6 showed earlier that HL60 cells react to violacein with bo...

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Augmentation of methylprednisolone-induced differentiation of myeloid leukemia cells by serine/threonine protein phosphatase inhibitors

Cited by 24 publications

References 17 publications

A promising action of riboflavin as a mediator of leukaemia cell death

A promising action of riboflavin as a mediator of leukaemia cell death

Protein phosphatase 2A-linked and -unlinked caspase-dependent pathways for downregulation of Akt kinase triggered by 4-hydroxynonenal

Molecular mechanism of violacein-mediated human leukemia cell death

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