TRAF1 is involved in the classical NF-κB activation and CD30-induced alternative activity in Hodgkin's lymphoma cells

Guo, Feng; Sun, Aining; Wang, Wenjuan; He, Jun; Hou, Jianquan; Zhou, Peng; Chen, Zixing

doi:10.1016/j.molimm.2009.05.178

Cited by 48 publications

(38 citation statements)

References 44 publications

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“…CD30 expression was also correlated with RELB and p52/RELB expression (Figure 2a). Activation of the alternative NF-κB pathway by CD30 has been shown in Hodgkin lymphoma 36 and anaplastic large-cell lymphoma, 37 and our results could suggest crosstalk between the alternative NF-κB pathway and CD30 signaling in DLBCL. DLBCL with p52 expression negatively correlated with BCL2 expression and BCL2 rearrangement (Figures 2b and c).…”

Section: Discussionsupporting

confidence: 70%

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Xu-Monette

et al. 2015

Modern Pathology

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Nuclear factor-κB (NF-κB) is a transcription factor with a well-described oncogenic role. Study for each of five NF-κB pathway subunits was only reported on small cohorts in diffuse large B-cell lymphoma (DLBCL). In this large cohort (n = 533) of patients with de novo DLBCL, we evaluated the protein expression frequency, gene expression signature, and clinical implication for each of these five NF-κB subunits. Expression of p50, p52, p65, RELB, and c-Rel was 34%, 12%, 20%, 14%, and 23%, whereas p50/p65, p50/c-Rel, and p52/RELB expression was 11%, 11%, and 3%, respectively. NF-κB subunits were expressed in both germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, but p50 and p50/c-Rel were associated with ABC-DLBCL. p52, RELB, and p52/ RELB expressions were associated with CD30 expression. p52 expression was negatively associated with BCL2 (B-cell lymphoma 2) expression and BCL2 rearrangement. Although p52 expression was associated with better progression-free survival (PFS) (P = 0.0170), singular expression of the remaining NF-κB subunits alone did not show significant prognostic impact in the overall DLBCL cohort. Expression of p52/RELB was associated with better overall survival (OS) and PFS (P = 0.0307 and P = 0.0247). When cases were stratified into GCB-and

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Section: Discussionsupporting

confidence: 70%

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Xu-Monette

et al. 2015

Modern Pathology

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“…It has been shown that stimulation of CD30 signaling activates alternative NF-kB signaling in HRS cells. 18,19 As expected, NF-kB p52 levels remained stable upon GSI XII treatment in CD30-stimulated L540cy cells (Figure 5b, left panel). As a result, loss of cell viability and apoptosis induction were alleviated in L540cy cells, as evidenced by CellTiter-Glo assay and analysis of poly-(ADP-ribose) polymerase cleavage (Figure 5b, left and right panels).…”

Section: Stimulation Of Alternative Nf-kb Signaling Rescues Hrs Cellssupporting

confidence: 77%

“…[15][16][17] Moreover, it has been demonstrated that stimulation of CD30 signaling either by agonistic receptor antibodies or by CD30 ligand induces alternative NF-kB signaling in HRS cells. 18,19 However, one study showed that CD30 signaling is absent in HRS cells. 20 Therefore, it remains largely unknown how the alternative NF-kB pathway is activated and whether it has a functional role in HRS cell growth and survival.…”

Section: Introductionmentioning

confidence: 99%

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

2011

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A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-jB (NF-jB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex contextdependent cross talk between Notch and NF-jB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the c-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-jB signaling, interfering with processing of the NF-jB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-jB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-jB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-jB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.

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“…The activation of CD30 by CD30L has previously been shown to cause ERK phosphorylation and NF-kB activation in HRS cell lines (29)(30)(31), and, indeed, we observed increased ERK1/2 phosphorylation and increases in the activity of the alternative NF-kB pathway upon lestaurtinib treatment in all analyzed HRS cell lines. TRAIL usually induces apoptosis in tumor cells via the TRAIL-Rassociated DISC.…”

Section: Discussionsupporting

confidence: 79%

“…CD30, a cell surface TNF receptor (TNFR) expressed by most HRS cells and HRS cell lines (28), has been shown to activate the MEK/ERK pathway and the classical and alternative NF-kB pathways upon binding of its ligand (29)(30)(31). The observed increases in ERK1/2 phosphorylation upon lestaurtinib treatment are thus most likely due to the CD30L upregulation.…”

Section: Lestaurtinib Activates the Alternative Nf-kb Pathway In Hrs mentioning

confidence: 99%

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

Holz

Janning

Renné

et al. 2013

Molecular Cancer Therapeutics

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Hodgkin-Reed/Sternberg (HRS) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases (RTK) in the majority of cases. Therefore, we tested whether tyrosine kinase inhibitors (TKI) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets, affected signaling pathways, and mechanisms of cell death and resistance. Sorafenib and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients. Sorafenib inhibited platelet-derived growth factor receptor (PDGFR) a, TRKA and RON, caused decreases in total and phosphorylated amounts of several signaling molecules, and provoked caspase-3-independent cell death, most likely due to endoplasmic reticulum stress as indicated by upregulation of GADD34 and GADD153 and phosphorylation of PERK. Lestaurtinib inhibited TRKA, PDGFRa, RON, and JAK2 and had only a cytostatic effect. Besides deactivation, lestaurtinib also caused activation of signaling pathways. It caused increases in CD30L and TRAIL expression, and CD30L/CD30 signaling likely led to the observed concomitant activation of extracellular signal-regulated kinase 1/2 and the alternative NF-kB pathway. These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF-kB activation as a potential novel mechanism of resistance toward TKIs.

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TRAF1 is involved in the classical NF-κB activation and CD30-induced alternative activity in Hodgkin's lymphoma cells

Cited by 48 publications

References 44 publications

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Evaluation of NF-κB subunit expression and signaling pathway activation demonstrates that p52 expression confers better outcome in germinal center B-cell-like diffuse large B-cell lymphoma in association with CD30 and BCL2 functions

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Induction of Endoplasmic Reticulum Stress by Sorafenib and Activation of NF-κB by Lestaurtinib as a Novel Resistance Mechanism in Hodgkin Lymphoma Cell Lines

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