Expression of Bcl‐2 family members and presence of Epstein–Barr virus in the regulation of cell growth and death in classical Hodgkin's lymphoma

Kim, L.H.; Nadarajah, Veera Sekaran; Peh, Suat‐Cheng; Poppema, Sibrand

doi:10.1111/j.0309-0167.2004.01829.x

Cited by 33 publications

(31 citation statements)

References 35 publications

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“…As inhibition of constitutive NF-kB activation is sufficient to trigger apoptosis of H-RS cells without stimulation of death receptor or cytotoxic agents, survival of H-RS cells appears to depend on a balance between anti-apoptotic and pro-apoptotic activities. In support of this notion, the present study confirmed the downregulation of c-FLIP and Bcl-xL, which are reported to be frequently expressed in H-RS cells upon blocking of NF-kB activity [21][22][23][24] (Figure 5c and d).…”

Section: Discussionsupporting

confidence: 89%

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IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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Constitutive nuclear factor kB (NF-kB) activation characterizes Hodgkin/Reed-Sternberg (H-RS) cells. Blocking constitutive NF-kB has been shown to be a potential strategy to treat Hodgkin lymphoma (HL). Here, for the first time we show that although constitutive NF-kB level of H-RS cell lines is very high, topoisomerase inhibitors further enhance NF-kB activation through IkB kinase activation in not only H-RS cell lines with wild-type IkBa, but also in those with IkBa mutations and lacking wild-type IkBa. Thus, both constitutive and inducible NF-kB are potential targets to treat HL. We also present the data that indicate the involvement of IkBb in NF-kB induction by topoisomerase inhibitors. A new NF-kB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) inhibited constitutive NF-kB activity and induced apoptosis of H-RS cell lines. DHMEQ also inhibited the growth of H-RS cells without significant systemic toxicity in a NOD/SCID/gc null (NOG) mice model. DHMEQ and topoisomerase inhibitors revealed enhancement of apoptosis of H-RS cells by blocking inducible NFkB. Results of this study suggest that both constitutive and inducible NF-kB are molecular targets of DHMEQ in the treatment of HL. The results also indicate that IkBb is involved in NF-kB activation in H-RS cells and IkBb substitutes for IkBa in H-RS cells lacking wild-type IkBa.

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Section: Discussionsupporting

confidence: 89%

“…[21][22][23][24] Bcl-xL and c-FLIP antagonize mitochondrial and membranous caspase activities. 25 We next examined changes in their expression upon DHMEQ treatment by Northern blotting and immunohistochemistry.…”

Section: Dhmeq-induced Apoptosis Involves Activation Of Caspases 3 8mentioning

confidence: 99%

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Watanabe

Dewan

Taira

et al. 2007

Laboratory Investigation

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“…Third, Bcl-2 degradation in the germinal center cells following their antigenic stimulation. 34 Our finding of Bcl-2 expression in the Hodgkin's and Reed-Sterenberg cells not only agrees with the previous studies 35,36 but also reflects their possible B cell lineage. 37,38 H/RS cells expressed Bcl-2 protein however the Bcl-2/JH gene rearrangement was undetectable in many cases of HD.…”

Section: A B C D E Fsupporting

confidence: 89%

Analysis of the Bcl-2 and p53 protein expression in the lymphoproliferative lesions in the upper Egypt

Hussein¹,

Al-Sabae²,

Georgis³

2005

Cancer Biology & Therapy

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Background: Lymphomagenesis involves poorly understood alterations in the proapoptotic and prosurvival molecules. In the Upper Egypt, the clinicopathologic and genetic characteristics (p53 and Bcl-2) of the lymphoproliferative lesions (reactive hyperplasia, RH; Non-Hodgkin's lymphoma, NHL and Hodgkin's disease, HD) is unknown.Objectives: To examine the lymphoproliferative lesions for: (1) their clinicopathologic features, (2) the p53, and Bcl-2 protein expression and (3) the correlation between the clinicopathologic features and the genetic alterations.Methods: p53 and Bcl-2 protein expression was immunohistochemically evaluated in 68 lesions including 47 NHL, 10 HD, and 11 RH. The average weighted scores reflecting staining intensity and the percentage of positive cells were calculated.Results: Clinically: 1) the mean age incidence gradually increased from HD to RH to NHL (16.1 ± 5.9, 36.6 ± 7.45 and 46.74 ± 3.2, p = 0.001) and 2) NHL and RH showed slight female (1.1:1) and male (1.2:1) sex predilection, respectively. Also, HD has male (2.3:1) sex predilection. The bcl-2 average weighted scores showed gradual downregulation with the transition from low to intermediate to high grade NHL (9.50 ± 1.12 > 6.67 ± 0.70 > 6.28 ± 0.83, p = 0.041). Alternatively, the p53 average weighted scores showed gradual upregulation with the transition from low to intermediate to high grade NHL (0.40 ± 0.22 < 1.72 ± 0.35 < 2.15 ± 0.52, p = 0.023). There was a negative correlation between bcl-2 and p53 protein expression in NHL (r = -0.221, p = 0.165). In HD, Reed-Sternberg cells and their variants showed positive and negative reactivity for Bcl-2 and p53 protein expression, respectively.Conclusions: In the Upper Egypt: (1) lymphoproliferative lesions had some peculiar clinicopathologic features and (2) Bcl-2 and p53 proteins are altered in the lymphoproliferative lesions.

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“…The finding supported that nasopharyngeal carcinoma (NPC) Bcl-2 expression can be independent of LMP-1 (Sarac et al, 2001), and that EBV up-regulation of apoptosis has no relation to Bcl-2 expression. In EBVassociated non-Hodgkin lymphomas, the T cell type is predominant (Takano et al, 1997), which corresponds to the finding (Kim et al, 2004) that EBV does not induce the up-regulation of Bcl-2 expression in classical Hodgkin's lymphoma. In addition, in EBV-positive natural killer cell lymphoma, Bcl-2 expression is not directly mediated by LMP-1 (Noguchi et al, 2001).…”

Section: Lmp-1 Specifically Up-regulates Bcl-2 Expressionsupporting

confidence: 81%

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Mao

2013

J. Zhejiang Univ. Sci. B

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Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world's population, is associated with malignant tumors such as Burkitt's lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

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Expression of Bcl‐2 family members and presence of Epstein–Barr virus in the regulation of cell growth and death in classical Hodgkin's lymphoma

Cited by 33 publications

References 35 publications

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

IκBα independent induction of NF-κB and its inhibition by DHMEQ in Hodgkin/Reed-Sternberg cells

Analysis of the Bcl-2 and p53 protein expression in the lymphoproliferative lesions in the upper Egypt

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

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