Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

Sanda, Takaomi; Asamitsu, Kaori; Ogura, Hiroka; Iida, Shinsuke; Utsunomiya, Atae; Ueda, Ryuzo; Okamoto, Takashi

doi:10.1038/sj.leu.2404129

Cited by 45 publications

(33 citation statements)

References 31 publications

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“…[9][10][11] The need for agents that kill HTLV-I-infected T cells is obvious and attempts to induce apoptosis by NF-jB inhibitors were successful. [12][13][14][15] Anti-ATL drug that targets other than NF-jB include the AP-1 and PI3K/Akt proteins. 11,[16][17][18][19] The molecular chaperone protein Hsp90 is involved in the folding, activation and assembly of a variety of proteins.…”

mentioning

confidence: 99%

Retracted: Inhibition of heat shock protein‐90 modulates multiple functions required for survival of human T‐cell leukemia virus type I‐infected T‐cell lines and adult T‐cell leukemia cells

Kawakami

Tomita

Okudaira

et al. 2007

Intl Journal of Cancer

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The molecular chaperone Hsp90 is involved in the stabilization and conformational maturation of many signaling proteins that are deregulated in cancers. The geldanamycin derivative 17-AAG is currently tested in clinical trials and known to inhibit the function of Hsp90 and promote the proteasomal degradation of its misfolded client proteins. ATL is a fatal malignancy of T lymphocytes caused by HTLV-I infection and remains incurable. Since Hsp90 is overexpressed in HTLV-I-infected T-cell lines and primary ATL cells, we analyzed the effects of 17-AAG on cell survival, apoptosis and expression of signal transduction proteins. HTLV-Iinfected T-cell lines and primary ATL cells were significantly more sensitive to 17-AAG in cell survival assays than normal PBMCs. 17-AAG induced the inhibition of cell cycle and apoptosis. These effects could be mediated by inactivation of NF-jB, AP-1 and PI3K/Akt pathways, as well as reduction of expression of proteins involved in the G 1 -S cell cycle transition and apoptosis. Proteasome inhibition interfered with 17-AAG-mediated signaling proteins depletion. Collectively, our results indicate that 17-AAG suppresses ATL cell survival through, at least in part, destabilization of several client proteins and suggest that 17-AAG is a potentially useful chemotherapeutic agent for ATL. ' 2007 Wiley-Liss, Inc.

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mentioning

confidence: 99%

Retracted: Inhibition of heat shock protein‐90 modulates multiple functions required for survival of human T‐cell leukemia virus type I‐infected T‐cell lines and adult T‐cell leukemia cells

Kawakami

Tomita

Okudaira

et al. 2007

Intl Journal of Cancer

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“…20 For apoptosis analysis, the cells were treated with or without HDACi for 18 h, and incubated with fluorescein isothiocyanate (FITC)-conjugated annexin V (MBL, Nagoya, Japan). The cell numbers of annexin V-positive cells were analyzed by flowcytometry (FACScan, BD Bioscience, San Jose, CA, USA) and CellQuest analysis program (BD Bioscience).…”

Section: Apoptosis and Cell Cycle Analysismentioning

confidence: 99%

“…A human acute T-cell leukemia cell line, Jurkat, ATL cell lines, MT-2, ATL-102 and ED-40515(À), chronic lymphocytic leukemia cell lines, MEC2 and MO1043, Burkitt's lymphoma cell lines, Raji and Daudi and multiple myeloma cell lines, U266, XG7, KM5, ILKM-2 and RPMI-8226 were used in this study as described previously. [20][21][22][23][24] For normal controls, peripheral blood mononuclear cells (PBMCs) were obtained from four independent healthy donors upon informed consent after the approval of Institutional Ethical Committee. All cells were cultured in RPMI-1640 medium, supplemented with 10% fetal bovine serum at 371C in a 5% CO 2 incubator.…”

Section: Introductionmentioning

confidence: 99%

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

et al. 2007

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Recent reports showing successful inhibition of cancer and leukemia cell growth using histone deacetylase inhibitor (HDACi) compounds have highlighted the potential use of HDACi as anti-cancer agents. However, high incidence of toxicity and low stability in vivo were observed with hydroxamic acid-based HDACi such as suberoylanilide hydroxamic acid (SAHA), thus limiting its clinical applicability. In this study, we found that a novel non-hydroxamate HDACi NCH-51 could inhibit the cell growth of a variety of lymphoid malignant cells through apoptosis induction, more effectively than SAHA. Activation of caspase-3, -8 and -9, but not -7 was detected after the treatment with NCH-51. Gene expression profiles showed that NCH-51 and SAHA similarly upregulated p21 and downregulated anti-apoptotic molecules including survivin, bcl-w and c-FLIP. Proteome analysis using two-dimensional electrophoresis revealed that NCH-51 upregulated anti-oxidant molecules including peroxiredoxin 1 and 2 and glutathione S-transferase at the protein level. Interestingly, NCH-51 induced reactive oxygen species (ROS) after 8 h whereas SAHA continuously declined ROS. Pretreatment with an antioxidant, N-acetyl-L-cysteine, abolished the cytotoxicity of NCH-51. These findings suggest that NCH-51 exhibits cytotoxicity by sustaining ROS at the higher level greater than SAHA. This study indicates the therapeutic efficacy of NCH-51 and novel insights for anti-HDAC therapy.

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“…To study the impact of Tax SUMOylation on the activation of a natural NF-B-regulated promoter, we quantified by real-time PCR the expression of ICAM-1, which has been reported to be induced by Tax in an NF-B-dependent manner (18). 293T cells were first transfected with the Ubc9-C93S mutant (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Non-SUMOylated Tax Protein Is Still Functional for NF-κB Pathway Activation

Pène

Waast

Bonnet

et al. 2014

J Virol

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Whether NF-B promoter transactivation by the human T-cell leukemia virus type 1 (HTLV-1) Tax protein requires Tax SUMOylation is still a matter of debate. In this study, we revisited the role of Tax SUMOylation using a strategy based on the targeting of Ubc9, the unique E2 SUMO-conjugating enzyme. We show that either a catalytically inactive form of Ubc9 (Ubc9-C93S) or Ubc9 small interfering RNA (siRNA) dramatically reduces Tax conjugation to endogenous SUMO-1 or SUMO-2/3, demonstrating that as expected, Tax SUMOylation is under the control of the catalytic activity of Ubc9. We further report that a non-SUMOylated Tax protein produced in 293T cells is still able to activate either a transfected or an integrated NF-B reporter promoter and to induce expression of an NF-B-regulated endogenous gene. Importantly, blocking Ubc9 activity in T cells also results in the production of a non-SUMOylated Tax that is still fully functional for the activation of a NF-B promoter. These results provide the definitive evidence that Tax SUMOylation is not required for NF-B-driven gene induction. IMPORTANCE Human T-cell leukemia virus type 1 is able to transform CD4؉ T lymphocytes. The viral oncoprotein Tax plays a key role in this process by promoting cell proliferation and survival, mainly through permanent activation of the NF-B pathway. Elucidating the molecular mechanisms involved in NF-B pathway activation by Tax is therefore a key issue to understand HTLV-1-mediated transformation. Tax SUMOylation was initially proposed to be critical for Tax-induced NF-B promoter activation, which was challenged by our later observation that a low-level-SUMOylated Tax mutant was still functional for activation of NF-B promoters. To clarify the role of Tax SUMOylation, we set up a new approach based on the inhibition of the SUMOylation machinery in Tax-expressing cells. We show that blocking the SUMO-conjugating enzyme Ubc9 abolishes Tax SUMOylation and that a non-SUMOylated Tax still activates NF-B promoters in either adherent cells or T cells.

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Induction of cell death in adult T-cell leukemia cells by a novel IκB kinase inhibitor

Cited by 45 publications

References 31 publications

Retracted: Inhibition of heat shock protein‐90 modulates multiple functions required for survival of human T‐cell leukemia virus type I‐infected T‐cell lines and adult T‐cell leukemia cells

Retracted: Inhibition of heat shock protein‐90 modulates multiple functions required for survival of human T‐cell leukemia virus type I‐infected T‐cell lines and adult T‐cell leukemia cells

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

A Non-SUMOylated Tax Protein Is Still Functional for NF-κB Pathway Activation

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