Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells

Abstract

Constitutively activated nuclear factor (NF)- IntroductionNuclear factor (NF)-B transcription factors regulate the expression of numerous genes that are necessary for proper functioning of the immune system and are key mediators of inflammatory responses to pathogens. 1,2 Furthermore, NF-B activity is associated with cell proliferation, transformation, and tumor development. [3][4][5] One of its most important functions is the activation of an antiapoptotic gene expression program. [6][7][8] The NF-B/Rel family consists of 5 members (p50, p52, p65 [RelA], c-Rel, and RelB), which can form various homodimeric or heterodimeric complexes. NF-B is activated by the release from cytoplasmic IB proteins and subsequently translocates into the nucleus. 1,2,9 Activation is triggered by signal-induced phosphorylation of IB␣, IB␤, and IB⑀ at N-terminal serines, which target the inhibitors for rapid degradation by the proteasome. [10][11][12] The IB kinase (IKK) complex, containing 2 protein kinases, IKK␣ and IKK␤, is responsible for the inducible phosphorylation of IBs and is the initial point of convergence for most stimuli that activate 12 Evidence linking aberrant Rel/NF-B activity to oncogenesis has emerged in recent years. Chromosomal rearrangements of genes coding for Rel/NF-B factors have been observed in many human hematopoietic and solid tumors. Several human cancer cell types are characterized by persistent nuclear NF-B activity, as a result of constitutive activation of upstream signaling kinases or mutations inactivating IB subunits. 5 Consistently, the viral oncoprotein v-Rel has transforming capacity in vitro and in vivo, 13 and several oncogenic viruses, such as human T-cell leukemia virus type I and Epstein-Barr virus (EBV), activate NF-B as part of the transformation process. 14,15 Recently, we have discovered deregulated NF-B activation in The molecular basis of constitutive NF-B in H/RS is not completely understood. In some H/RS cell lines and in biopsy samples from patients with relapsed HD, mutations in the IB␣ gene may contribute to constitutive NF-B activation. These mutations produce nonfunctional or unstable IB␣ proteins, missing various portions of the ankyrin domain and the C-terminal region. [22][23][24][25][26] However, most HD cell lines and primary neoplastic cells lack mutations in the ib␣ gene, and constitutive NF-B activity could also be observed in cell lines with wild-type IB␣ alleles. 25 In all cases examined, IKKs were constitutively activated, resulting in rapid degradation of IB␣ proteins and indicating ongoing signal transduction. 25 Because HD is often associated with EBV, the EBV-encoded latent membrane protein-1 may activate NF-B in these cases by promoting IB␣ turnover. 27 However, constitutive IKK activation was also observed in EBV Ϫ cell lines. 25 Interestingly, H/RS cells strongly express CD30 and CD40, 2 members of the tumor necrosis factor (TNF) receptor family that both can activate NF-B. [28][29][30][31][32][33] From the Max Delbrü ck Center for Molecular Medicine; HepaVec...

NF-κB-independent sensitization of glioblastoma cells for TRAIL-induced apoptosis by proteasome inhibition

“…Role of NF-jB in apoptosis of glioblastoma K La Ferla-Brühl et al reported to trigger massive spontaneous apoptosis in Hodgkin's lymphoma (Hinz et al, 2001), these findings point to a differential role of NF-kB in regulating cell survival and apoptosis in glioblastoma compared to other cancers, for example of the hematopoetic system such as Hodgkin's lymphoma. In addition to regulate cell survival and death under steady-state conditions in the absence of an external stimulus, NF-kB has also been implied to mediate chemoresistance, that is in response to cytotoxic stimuli.…”

“…NF-kB target genes include various antiapoptotic proteins (Karin et al, 2002). Constitutive NF-kB activation has been described in various cancers of hematopoietic and epithelial origin, for example Hodgkin's lymphoma, breast cancer, lung cancer, melanoma and pancreatic cancer, where it has been implicated in conferring chemoresistance (Wang et al, 1999;Biswas et al, 2000;Huang et al, 2000;Hinz et al, 2001;Jiang et al, 2001). Inhibition of NF-kB signaling, for example by overexpression of non-degradable IkBa mutants (IkBa superrepressor) or by proteasome inhibitors that prevent IkBa degradation, has been reported to sensitize tumor cells to apoptosis induced by TNFa or anticancer agents (Jeremias and Debatin, 1998;Karin et al, 2004).…”

Lymphocyte-rich classical Hodgkin's lymphoma: distinctive tumor and microenvironment markers

“…10 NF-kB activation is considered to be an important survival factor for mononuclear Hodgkin's cells and multinucleated Reed-Sternberg cells in classical Hodgkin's lymphoma, whereby the inactivation of factor NF-kB in Hodgkin's lymphoma cell lines leads to the apoptosis of neoplastic cells. 13,14 Different expression patterns of NF-kB subunits and related molecular factors have been shown in classical Hodgkin's lymphoma and nodular lymphocyte-predominant Hodgkin's lymphoma, with c-Rel protein, Rel-B, p-50, TRAF1, and MUM-1 being significantly more frequently expressed in the former. Our results are similar, supporting the hypothesis that there is a low or null degree of NFkB activation in nodular lymphocyte-predominant Hodgkin's lymphoma.…”

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…For instance, proliferation and survival of Hodgkin/Reed-Sternberg cells is blocked when NF-kB is inhibited by IkBa expression (Bargou et al, 1997). Moreover, inhibition of NF-kB in Hodgkin/Reed-Sternberg cells leads to the loss of expression of antiapoptotic effectors A1/Bfl-1, cellular-inhibitor of apoptosis 2 (c-IAP2), tumor necrosis factor receptor-associated factor1 and Bcl-xL (Hinz et al, 2001). Finally, another mechanism whereby NF-kB may block cell death is through its ability to suppress persistent c-Jun NH 2 -terminal kinase (JNK) activation and the generation of reactive oxygen species (see Luo et al, 2005;Bubici et al, 2006).…”