Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression

Bleumink, Marc; Köhler, Rebecca; Giaisi, Marco; Proksch, Peter; Krammer, Peter H.; Li‐Weber, Min

doi:10.1038/cdd.2010.99

Cited by 65 publications

(77 citation statements)

References 38 publications

(93 reference statements)

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“…It is conceivable that viral proteins have differing effects on cell survival, depending on the differentiation and activation status of the host cell. Our data on primary cells agree with observations that HTLV-1-infected T cell lines express high levels of Fas, but are resistant to Fas-L-induced apoptosis [34][35][36] and express FAP-1 (Fas inhibitor) [37]. Regardless of the observed resistance to Fas-induced apoptosis, Tax expression increased the sensitivity of peptide-loaded CD4 + cells to lysis by CTLs specific for an unrelated virus, EBV.…”

Section: Discussionsupporting

confidence: 81%

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Rowan¹,

Suemori²,

Fujiwara³

et al. 2014

Retrovirology

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Background: Immunogenetic evidence indicates that cytotoxic T lymphocytes (CTLs) specific for the weak CTL antigen HBZ limit HTLV-1 proviral load in vivo, whereas there is no clear relationship between the proviral load and the frequency of CTLs specific for the immunodominant antigen Tax. In vivo, circulating HTLV-1-infected cells express HBZ mRNA in contrast, Tax expression is typically low or undetectable. To elucidate the virus-suppressing potential of CTLs targeting HBZ, we compared the ability of HBZ-and Tax-specific CTLs to lyse naturally-infected cells, by co-incubating HBZ-and Tax-specific CTL clones with primary CD4 + T cells from HLA-matched HTLV-1-infected donors. We quantified lysis of infected cells, and tested whether specific virus-induced host cell surface molecules determine the susceptibility of infected cells to CTL-mediated lysis.

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Section: Discussionsupporting

confidence: 81%

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Rowan¹,

Suemori²,

Fujiwara³

et al. 2014

Retrovirology

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“…To measure the time resolved gene responses to Roc-A, RNA was isolated from Roc-A-treated (50 nM) normal T and Jurkat T cells at t 5 [0, 1,2,3,4,6,8,10,14,20,28,36] and t 5 [0. 5,1,2,3,4,5,6,7,8,10,12,14,16,20,24,28,32,36] hr, respectively. The quality of total RNA was controlled with an Agilent 2100 Bioanalyzer (Agilent Technologies GmbH, Berlin, Germany).…”

Section: Rna Preparation and Dna Microarray Analysismentioning

confidence: 99%

“…8,[10][11][12] One can predict that translation inhibition would consequently lead to downregulation of protein expression, particularly of those proteins having a short half-life such as CDK4, cyclin D and Cdc25. 1,[16][17][18][19] However, we noticed that Cdc25A was degraded upon Roc-A treatment with a much faster rate (with a half-life of less than 15 min) than Cdc25B, CDK4, CDK6 and cyclin D3 (Fig.…”

Section: Roc-a Suppresses Expression Of Key Proteins Involved In G1-smentioning

confidence: 99%

“…8 Hereafter, two independent studies showed that Roc inhibits protein synthesis by either suppressing the MEK-ERK activity leading to inactivation of the translation initiation factor 4E (eIF4E) or stimulating RNA-binding properties of eIF4A resulting in prevention of incorporation of free eIF4A into the eIF4F complex. [9][10][11] Recently, we have identified that prohibitin (PHB) 1 and 2, which are required for activation of the Ras-CRaf-MEK-ERK signaling pathway, are direct targets of Roc. 12 Blocking PHB function by Roc resulted in down-regulation of cyclin D3, CDK4, CDK6 and Cdc25A.…”

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confidence: 99%

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The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

et al. 2013

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Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over-expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide-A (Roc-A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1-S phase. Roc-A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc-A can induce a rapid degradation of Cdc25A by activation of the ATM/ATRChk1/Chk2 checkpoint pathway. However, Roc-A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc-A by a time-resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc-A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc-A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

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“…It has been reported that three splice variants of c-FLIP (c-FLIP L , c-FLIP R , and c-FLIP S ) can be detected at the protein level and that the expression of c-FLIP is regulated through multiple pathways, such as the MAP kinase, phosphatidylinositol 3-kinase (PI3K), and NF-B pathways (33)(34)(35). It has been demonstrated that the expression of c-FLIP is increased in ATL cells and HTLV-1-infected Tax-expressing T cells and that this increase contributes to the resistance of these cells to FasL-and TRAIL-induced apoptosis (25,26,36).…”

mentioning

confidence: 99%

Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

Wang

Zhou

Shi

et al. 2014

J Virol

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The human T-cell leukemia virus type 1 (HTLV-1) Tax protein is considered to play a central role in the process that leads to adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 Tax IMPORTANCEOur study reveals that Tax-deregulated autophagy is a protective mechanism for DR-mediated apoptosis. The molecular mechanism of Tax-induced autophagy is also illuminated, which is different from Tax-increased c-FLIP. Tax can be degraded via manipulation of autophagy and TRAIL-induced apoptosis. These results outline a complex regulatory network between and among apoptosis, autophagy, and Tax and also present evidence that autophagy represents a new possible target for therapeutic intervention for the HTVL-1 related diseases.

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Rocaglamide breaks TRAIL resistance in HTLV-1-associated adult T-cell leukemia/lymphoma by translational suppression of c-FLIP expression

Cited by 65 publications

References 38 publications

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

Cytotoxic T lymphocyte lysis of HTLV-1 infected cells is limited by weak HBZ protein expression, but non-specifically enhanced on induction of Tax expression

The natural anticancer compound rocaglamide selectively inhibits the G1-S-phase transition in cancer cells through the ATM/ATR-mediated Chk1/2 cell cycle checkpoints

Human T-Cell Leukemia Virus Type 1 Tax-Deregulated Autophagy Pathway and c-FLIP Expression Contribute to Resistance against Death Receptor-Mediated Apoptosis

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