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  • Cho, Dae-Ho  (7)
  • Medicine  (7)
  • 1
    Online Resource
    Online Resource
    ROS-p38 MAPK-Fas/Fas Ligand-Linked Cascade Regulate Bax Translocation and Calcium Redistribution in Salubrinal-Induced Apoptosis of EBV-Transformed B Cells (46.49)
    The American Association of Immunologists ; 2012
    In:  The Journal of Immunology Vol. 188, No. 1_Supplement ( 2012-05-01), p. 46.49-46.49
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 188, No. 1_Supplement ( 2012-05-01), p. 46.49-46.49
    Abstract: The small molecule salubrinal has antiviral activity against herpes simplex virus-1 (HSV-1) and inhibits dephosphorylation of eIF2 alpha. Salubrinal prevents vulnerable cells from going down the cell-death pathway and is deeply associated with ER stress. The Epstein-Barr Virus (EBV), also called human herpesvirus 4 (HHV-4), is a virus of the herpes family (which includes herpes simplex virus) and is one of the most common viruses in humans. However, maintaining hyper-phosphorylated eIF2α state with high doses of salubrinal treatment promotes apoptosis in some cancer cells. In this report, salubrinal inhibited proliferation and induced apoptosis of EBV-transformed B cells in both dose and time dependent manner. Notably, salubrinal induced ROS generation and p38 MAPK activation, which then induced expression of FasL. Moreover, salubrinal subsequently led to activation of caspases, calcium redistribution, Bax translocation, cytochrome c release, and apoptosis. Caspase inhibitors (z-VAD, z-IETD, and z-DEVD), p38 MAPK inhibitor (SB203580) and ROS inhibitor (NAC) recovered salubrinal-induced apoptosis. ZB4, an antagonistic anti-fas Ab, and SB203580 effectively blocked apoptosis without exerting any influence on ROS generation. These findings suggest that salubrinal may be a novel therapeutic approach for EBV-associated malignant diseases.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.188.Supp.46.49
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2012
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Sorafenib induces apoptosis through reactive oxygen species production, JNK/p38 MAPK activation, and suppression of Akt/NF-kB signaling in EBV-transformed B cells (P2088)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 132.34-132.34
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 132.34-132.34
    Abstract: Sorafenib (SRF), the multiple tyrosine kinase inhibitor, is known as a potential targeted drug that may have antitumor activity against various cancers, but the roles of SRF in EBV-transformed B cells remain unclear. Here, we investigated the in vitro cytotoxic effects of SRF on EBV-transformed B cells and the underlying mechanism such as the changes in oxidative stress and MAPKs signaling, which are closely associated with cell death-signaling transduction pathways, in EBV-transformed B cells treated with SRF. We first observed that SRF significantly decreased the cell viability of EBV-transformed B cells in a dose-dependent manner. SRF induced the generation of reactive oxygen species (ROS), translocation of Bax into mitochondria, disruption of mitochondrial membrane potential, activation of caspase-9, -3, and PARP, and subsequent apoptosis. Moreover, we found that SRF exposure activated the phosphorylation of JNK and p38 MAPK and suppressed the phosphorylation of PI3K p85 and Akt. In particular, SRF diminished nuclear localization of NF-κB in EBV-transformed B cells. These results demonstrate that SRF induces apoptosis through ROS production, ER stress, and mitochondrial-dependent pathway in EBV-transformed B cells. Taken together, these findings provide an overview of the molecular signaling pathway driving SRF-mediated cell death in EBV-transformed B cells and suggest SRF could be a potential therapeutic drug for the treatment of EBV-transformed B cells.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.132.34
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Engagement of CD47 induces G1 arrest in EBV-transformed B cells by controlling CDK-cyclin-CDKi and activating p38 MAPK/JNK pathway (P2149)
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 190, No. 1_Supplement ( 2013-05-01), p. 170.31-170.31
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 190, No. 1_Supplement ( 2013-05-01), p. 170.31-170.31
    Abstract: CD47 possesses a variety of anti-tumor, anti-angiogenic, and anti-metastatic properties in several tumors, but its roles on EBV-transformed B cells are still not fully understood. Here we first observed that EBV infection induced CD47 expression on B cells surface, and CD47 stimulation of EBV-transformed B cells with anti-CD47 mAb (B6H12) reduced cell proliferation and induced the cell cycle arrest at G1-phase. We showed that CD47-induced G1-phase arrest was mediated through increased expression of CDKi (p16INK4a, p21WAF1, and p53), a simultaneous decreased expression in CDK2, 4, 6 and cyclin D1, D2 and E and enhanced binding of CDKi-CDK. Among the relevant pathways, CD47 mAb induced outstanding activation of p38 MAPK and JNK, whereas phosphorylation of Akt and ERK1/2 were both reduced. In particular, p38 inhibitor SB203580 and JNK inhibitor SP600125 powerfully blocked the decreased expression of CDK and the increased expression of CDKi and dramatically suppressed binding of phospho-p38-CDKi. Accordingly, these data demonstrate that the p38 MAPK and JNK pathway participates in CDKi induction, subsequently leading to a decrease in the levels of cyclin D1-CDK4/6 and cyclin E-CDK2 complexes and CD47-dependent EBV-transformed B cell growth inhibition. In conclusion, these findings concerning the molecular mechanisms of CD47 signaling in EBV-transformed B cells provides a theoretical basis for clinical approaches for the use of therapeutic agents in treating EBV-associated tumors.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.190.Supp.170.31
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    Cell cycle arrest induced by engagement of B7-H4 on Epstein-Barr virus-positive B-cell lymphoma cell lines
    Wiley ; 2009
    In:  Immunology Vol. 128, No. 3 ( 2009-11), p. 360-368
    Details
    In: Immunology, Wiley, Vol. 128, No. 3 ( 2009-11), p. 360-368
    Type of Medium: Online Resource
    ISSN: 0019-2805 , 1365-2567
    URL: Issue
    URL: Article
    DOI: 10.1111/imm.2009.128.issue-3
    DOI: 10.1111/j.1365-2567.2009.03111.x
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2009
    detail.hit.zdb_id: 2006481-0
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  • 5
    Online Resource
    Online Resource
    Endoplasmic reticulum stress-mediated apoptosis of EBV-transformed B cells by CD70 signaling is dependent upon generation of reactive oxygen species and activation of p38 MAPK and JNK pathway (66.23)
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 1_Supplement ( 2011-04-01), p. 66.23-66.23
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 1_Supplement ( 2011-04-01), p. 66.23-66.23
    Abstract: CD70 is expressed in normal activated immune cells as well as in several types of tumors. It has been established that anti-CD70 mAb induces complement-dependent death of CD70+ tumor cells, but how anti-CD70 mAb affects the intrinsic signaling is poorly defined. In this report, we show that ligation of CD70 expressed on EBV-transformed B cells induced production of reactive oxygen species (ROS) and subsequent apoptosis. We observed an early expression of endoplasmic reticulum (ER) stress response genes that preceded the release of apoptotic molecules from mitochondria and cleavage of caspases. CD70-induced apoptosis was inhibited by ER stress inhibitor salubrinal, ROS quencher NAC, and Ca2+ chelator BAPTA. We supposed that ROS generation might be the first event because NAC blocked increases of ROS and Ca2+, but BAPTA did not block ROS. We also found that CD70 stimulation activated JNK and p38. JNK inhibitor and p38 inhibitor blocked upregulation of ER stress-related genes and cleavage of caspases. Inhibition of ROS generation blocked phosphorylation of JNK and p38 and induction of ER stress-related genes. Taken together, we concluded that cross-linking of CD70 on EBVt- B cells triggered ER stress-mediated apoptosis via ROS generation and JNK and p38 MAPK activation. Our report reveals alternate mechanisms of direct apoptosis through CD70 signaling and provides data supporting CD70 as a viable target for an Ab-based therapy against EBV-related tumors.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.186.Supp.66.23
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    Endoplasmic Reticulum Stress-Mediated Apoptosis of EBV-Transformed B Cells by Cross-Linking of CD70 Is Dependent upon Generation of Reactive Oxygen Species and Activation of p38 MAPK and JNK Pathway
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 185, No. 12 ( 2010-12-15), p. 7274-7284
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 185, No. 12 ( 2010-12-15), p. 7274-7284
    Abstract: CD70 is expressed in normal activated immune cells as well as in several types of tumors. It has been established that anti-CD70 mAb induces complement-dependent death of CD70+ tumor cells, but how anti-CD70 mAb affects the intrinsic signaling is poorly defined. In this report, we show that ligation of CD70 expressed on EBV-transformed B cells using anti-CD70 mAb induced production of reactive oxygen species (ROS) and subsequent apoptosis. We observed an early expression of endoplasmic reticulum (ER) stress response genes that preceded the release of apoptotic molecules from the mitochondria and the cleavage of caspases. CD70-induced apoptosis was inhibited by pretreatment with the ER stress inhibitor salubrinal, ROS quencher N-acetylcysteine, and Ca2+ chelator BAPTA. We supposed that ROS generation might be the first event of CD70-induced apoptosis because N-acetylcysteine blocked increases of ROS and Ca2+, but BAPTA did not block ROS generation. We also found that CD70 stimulation activated JNK and p38 MAPK. JNK inhibitor SP600125 and p38 inhibitor SB203580 effectively blocked upregulation of ER stress-related genes and cleavage of caspases. Inhibition of ROS generation completely blocked phosphorylation of JNK and p38 MAPK and induction of ER stress-related genes. Taken together, we concluded that cross-linking of CD70 on EBV-transformed B cells triggered ER stress-mediated apoptosis via ROS generation and JNK and p38 MAPK pathway activation. Our report reveals alternate mechanisms of direct apoptosis through CD70 signaling and provides data supporting CD70 as a viable target for an Ab-based therapy against EBV-related tumors.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1001547
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    Melphalan-Induced Apoptosis of EBV-Transformed B Cells through Upregulation of TAp73 and XAF1 and Nuclear Import of XPA
    The American Association of Immunologists ; 2013
    In:  The Journal of Immunology Vol. 191, No. 12 ( 2013-12-15), p. 6281-6291
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 191, No. 12 ( 2013-12-15), p. 6281-6291
    Abstract: Melphalan (Mel) is widely used to treat patients with hematologic cancer, including multiple myeloma, but its mechanism of action in EBV-transformed B cells is poorly described. In this study, we demonstrate a novel mechanism by which transcriptionally active p73 (TAp73) induces translocation of X-linked inhibitor of apoptosis protein–associated factor 1 (XAF1) and xeroderma pigmentosum group A (XPA) during apoptosis caused by Mel treatment. We observed that Mel induced significant generation of reactive oxygen species (ROS) and subsequent apoptosis, as well as an early phosphorylation of p38 MAPK that preceded expression of the mitochondria membrane potential disruption–related molecules and the cleavage of caspases. In particular, Mel led to upregulation of TAp73, XAF1, and Puma and induced XPA nuclear import and translocation of Bax into mitochondria. Mel-induced apoptosis was inhibited by pretreatment with the ROS scavenger 4-amino-2,4-pyrrolidine-dicarboxylic acid (APDC) and the p38 MAPK inhibitor SB203580. We supposed that ROS generation might be the first event in Mel-induced apoptosis, because APDC blocked the increase in ROS, p38 MAPK, and TAp73, but SB203580 did not block ROS generation. Moreover, Mel elicited activation of ATR, and APDC inhibited phosphorylation of ATR but not SB203580. APDC and SB203580 completely blocked XPA and Bax translocation. We conclude that Mel promotes TAp73-mediated XAF1 and Puma expression via ROS generation and ATR/p38 MAPK pathway activation, thereby triggering apoptosis. Our results provide evidence of a novel alternate regulatory mechanism of TAp73 and reveal that Mel may be a therapeutic drug for curing EBV-related malignancies.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1203442
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2013
    detail.hit.zdb_id: 1475085-5
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