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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to induce angiogenesis, apoptosis in tumor cells, and NF-kappaB activation through binding to its receptor, fibroblast growth factor-inducible 14. We have identified TWEAK as an inducer of constitutive NF-kappaB activation by expression cloning, and we report here sequential regulation by TWEAK of two separate signaling cascades for NF-kappaB activation, the NF-kappaB essential modulator-dependent and -independent signaling pathways. Upon TWEAK stimulation, IkappaBalpha is rapidly phosphorylated, generating NF-kappaB DNA-binding complexes containing p50 and RelA in a manner dependent on the canonical IkappaB kinase complex. Unlike TNF-alpha, TWEAK stimulation results in prolonged NF-kappaB activation with a transition of the DNA-binding NF-kappaB components from RelA- to RelB-containing complexes by 8 h, and the latter remained active in binding at least until 24 h post-stimulation. This long lasting activation is accompanied by the proteasome-mediated processing of NF-kappaB2/p100, which does not depend on the NF-kappaB essential modulator but requires IkappaB kinase 1 and functional NF-kappaB-inducing kinase activity. Finally, we show that fibroblast growth factor-inducible 14 with a mutation at its TNF receptor-associated factor (TRAF)-binding site cannot activate NF-kappaB and that TWEAK fails to induce the p100 processing and IkappaBalpha phosphorylation in cells deficient for TRAF2 and TRAF5. Our results thus identify TWEAK as a novel physiological regulator of the non-canonical pathway for NF-kappaB activation.
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PMID:TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. 1284 22

We have previously demonstrated the anti-tumor activity of nitrosylcobalamin (NO-Cbl), an analog of vitamin B12 that delivers nitric oxide (NO) and increases the expression of tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) and its receptors in human tumors. The specific aim of this study was to examine whether NO-Cbl could sensitize drug-resistant melanomas to Apo2L/TRAIL. Antiproliferative effects of NO-Cbl and Apo2L/TRAIL were assessed in malignant melanomas and non-tumorigenic melanocyte and fibroblast cell lines. Athymic nude mice bearing human melanoma A375 xenografts were treated with NO-Cbl and Apo2L/TRAIL. Apoptosis was measured by TUNEL and confirmed by examining levels and activity of key mediators of apoptosis. The activation status of NF-kappa B was established by assaying DNA binding, luciferase reporter activity, the phosphorylation status of I kappa B alpha, and in vitro IKK activity. NO-Cbl sensitized Apo2L/TRAIL-resistant melanoma cell lines to growth inhibition by Apo2L/TRAIL but had minimal effect on normal cell lines. NO-Cbl and Apo2L/TRAIL exerted synergistic anti-tumor activity against A375 xenografts. Treatment with NO-Cbl followed by Apo2L/TRAIL induced apoptosis in Apo2L/TRAIL-resistant tumor cells, characterized by cleavage of caspase-3, caspase-8, and PARP. NO-Cbl inhibited IKK activation, characterized by decreased phosphorylation of I kappa B alpha and inhibition of NF-kappa B DNA binding activity. NO-Cbl suppressed Apo2L/TRAIL- and TNF-alpha-mediated activation of a transfected NF-kappa B-driven luciferase reporter. XIAP, an inhibitor of apoptosis, was inactivated by NO-Cbl. NO-Cbl treatment rendered Apo2L/TRAIL-resistant malignancies sensitive to the anti-tumor effects of Apo2L/TRAIL in vitro and in vivo. The use of NO-Cbl and Apo2L/TRAIL capitalizes on the tumor-specific properties of both agents and represents a promising anti-cancer combination.
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PMID:Suppression of NF-kappa B survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL. 3178 79

NF-kappa B is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-kappa B prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-kappa B pathway with I kappa B overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-kappa B activity, suppressed PTEN gene expression in IKK beta(+/+) cells but not in IKK beta(-/-) cells, which are deficient in the NF-kappa B activation pathway. These findings indicated that NF-kappa B activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-kappa B. The mechanism underlying suppression of PTEN expression by NF-kappa B was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-kappa B transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-kappa B. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-kappa B.
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PMID:Suppression of PTEN expression by NF-kappa B prevents apoptosis. 1472 49

The importance of the IkappaB kinase (IKK)/NF-kappaB signaling pathway in immunoregulatory functions is well accepted. However, the relevance of IKK and NF-kappaB in tumor maintenance, tumor promotion and possibly even in tumor initiation is becoming more evident. Activation of the IKK/NF-kappaB signaling pathway leads to the induction of target genes that can interfere with apoptosis, cell cycle regulation, cell invasion and metastatic growth as well as radio- and chemotherapy. By possibly bridging inflammation and cancer NF-kappaB might also contribute to tumorigenesis. Several natural compounds and synthetic drugs that are able to inhibit the IKK/NF-kappaB activation pathway have been shown to either prevent cancer or to inhibit cell growth in animal models. However, these compounds do not selectively inhibit any of the NF-kappaB activation pathways. Furthermore, general inhibition of NF-kappaB might lead to immunodeficiency. The investigation of the different NF-kappaB signaling pathways in different cell types and their role in certain diseases is therefore needed to evaluate the most successful therapeutic strategies.
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PMID:The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. 1501 24

Antimicrotubule Vinca alkaloids, such as vinblastine and vincristine, interfere with the dynamics of microtubules and have shown significant cell killing activity in a variety of tumor cells through induction of apoptosis. The mechanism by which Vinca alkaloids induce apoptosis is not entirely clear. In this study, we found that glucocorticoids inhibit Vinca alkaloid-induced apoptosis without affecting G(2)-M arrest in human breast cancer BCap37 cells and human epidermoid tumor KB cells, suggesting that Vinca alkaloid-induced apoptosis may occur via a pathway independent of cell cycle arrest. Further analyses indicated that Vinca alkaloids cause significant degradation of IkappaBalpha, which in turn results in nuclear factor-kappaB (NF-kappaB) activation. Transfection of antisense IkappaBalpha in BCap37 cells sensitizes Vinca alkaloid-induced apoptosis. Moreover, in vitro kinase assays show that the activity of IkappaB kinase (IKK) was activated by Vinca alkaloids and was not affected by glucocorticoids. Stable transfection of dominant-negative deletional mutant IkappaBalpha, which is insensitive to IKK-mediated phosphorylation and degradation, resulted in the inhibition of Vinca alkaloid-induced NF-kappaB activation and reduced sensitivity of tumor cells to Vinca alkaloid-induced apoptosis. These findings suggest that the NF-kappaB/IkappaB signaling pathway may contribute to the mediation of Vinca alkaloid-induced apoptosis in human tumor cells.
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PMID:Regulation of Vinca alkaloid-induced apoptosis by NF-kappaB/IkappaB pathway in human tumor cells. 1502 47

The nuclear factor of kappaB (NF-kappaB) family of heterodimeric transcription factors plays an instrumental role in immune, inflammatory, and stress responses. NF-kappaB induces the expression of diverse target genes that promote cell cycle progression, regulate apoptosis, and facilitate cell adhesion, angiogenesis, and metastasis. Given the ability of NF-kappaB to influence these cardinal features of neoplastic transformation, it is no surprise that tumor cells of almost every tissue type acquire the ability to constitutively activate NF-kappaB via a host of diverse genetic alterations and viral proteins. The activation of NF-kappaB not only enables malignant transformation and tumor progression, but also provides a mechanism by which tumor cells escape immune surveillance and resist therapy. NF-kappaB may be inhibited by targeting either the apical signaling proteins responsible for its activation in specific types of cancer, the downstream kinases (IkappaB kinase and casein kinase 2) at which NF-kappaB-activating signaling pathways converge, the proteasome-mediated degradation of the inhibitor of kappaB (IkappaB) proteins, or the transcriptional activity of Rel proteins. Since NF-kappaB inhibitors can sensitize tumor cells to apoptosis signaling pathways activated by death receptors, interferons, and immune effector cells, they hold enormous promise for the development of effective combinatorial regimens against a wide spectrum of hematologic and epithelial malignancies.
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PMID:NF-kappaB in cancer--a friend turned foe. 1507 71

Two recent reports reveal new roles for FoxO proteins in cell proliferation and tumorigenesis. Seoane and colleagues show that FoxO proteins play key roles in the TGFbeta-dependent activation of p21Cip1 by partnering with Smad3 and Smad4. FoxG1, a protein from a distinct Fox subfamily, binds FoxO/Smad complexes and blocks p21Cip1 expression. These interactions establish a relationship between the PI3K pathway, FoxG1, and the TGFbeta/Smad pathways. The second report identifies IkappaB kinase as a negative regulator of FoxO proteins, suggesting a mechanism for relieving negative regulation of cell cycle and promoting tumor cell proliferation.
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PMID:FoxO: linking new signaling pathways. 1514 89

Adult T-cell leukemia (ATL) is a fatal T-cell malignancy that arises long after infection with human T-cell leukemia virus type I (HTLV-I). We reported previously that nuclear factor-kappaB (NF-kappaB) was constitutively activated in ATL cells, although expression of the viral proteins was barely detectable, including Tax, which was known to persistently activate NF-kappaB. Here we demonstrate that ATL cells that do not express detectable Tax protein exhibit constitutive IkappaB kinase (IKK) activity. Transfection studies revealed that a dominant-negative form of IKK1, and not of IKK2 or NF-kappaB essential modulator (NEMO), suppressed constitutive NF-kappaB activity in ATL cells. This IKK activity was accompanied by elevated expression of p52, suggesting that the recently described noncanonical pathway of NF-kappaB activation operates in ATL cells. We finally show that specific inhibition of NF-kappaB by a super-repressor form of IkappaBalpha (SR-IkappaBalpha) in HTLV-I-infected T cells results in cell death regardless of Tax expression, providing definitive evidence of an essential role for NF-kappaB in the survival of ATL cells. In conclusion, the IKK complex is constitutively activated in ATL cells through a cellular mechanism distinct from that of Tax-mediated IKK activation. Further elucidation of this cellular mechanism should contribute to establishing a rationale for treatment of ATL.
Neoplasia
PMID:Tax-independent constitutive IkappaB kinase activation in adult T-cell leukemia cells. 1515 39

The transcription factor NF-kappaB regulates genes involved in inflammatory and immune responses, tumorigenesis, and apoptosis. In contrast to the pleiotropic stimuli that lead to its positive regulation, the known signaling mechanisms that underlie the negative regulation of NF-kappaB are very few. Recent studies have identified the tumor suppressor CYLD, loss of which causes a benign human syndrome called cylindromatosis, as a key negative regulator for NF-kappaB signaling by deubiquitinating tumor necrosis factor (TNF) receptor-associated factor (TRAF) 2, TRAF6, and NEMO (NF-kappaB essential modulator, also known as IkappaB kinase gamma). However, how CYLD is regulated remains unknown. The present study revealed a novel autoregulatory feedback pathway through which activation of NF-kappaB by TNF-alpha and bacterium nontypeable Haemophilus influenzae (NTHi) induces CYLD that in turn leads to the negative regulation of NF-kappaB signaling. In addition, TRAF2 and TRAF6 appear to be differentially involved in NF-kappaB-dependent induction of CYLD by TNF-alpha and NTHi. These findings provide novel insights into the autoregulation of NF-kappaB activation.
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PMID:NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. 1522 92

A subset of quiescent memory CD4 T cells harboring integrated but transcriptionally silent proviruses poses a currently insurmountable barrier to the eradication of the human immunodeficiency virus (HIV) in infected patients. Induction of HIV gene expression in these latently infected cells by immune activating agents has been proposed as one approach to confer sensitivity to antiretroviral therapy. Interest has recently focused on the non-tumor-promoting phorbol ester, prostratin, as a potential agent to activate latent HIV proviruses. Using multiple Jurkat T cell lines containing integrated but transcriptionally latent HIV proviruses (J-Lat cells), we now demonstrate that prostratin effectively activates HIV gene expression in these latently infected cells. We further show that prostratin acts by stimulating IKK-dependent phosphorylation and degradation of IkappaBalpha, leading to the rapid nuclear translocation of NF-kappaB and activation of the HIV-1 long terminal repeat in a kappaB enhancer-dependent manner. In contrast, NFAT and AP-1 are not induced by prostratin. Using chromatin immunoprecipitation assays to identify host transcription factors recruited to the latent HIV-1 promoter in living cells, we find that prostratin induces RelA binding. Analysis of potential upstream signal transducers demonstrates that prostratin stimulates membrane translocation of classical, novel, and atypical protein kinase C (PKC) isoforms. Studies with isoform-specific PKC inhibitors suggest that the novel PKCs play a particularly prominent role in the prostratin response. These findings provide new insights into the molecular pathway through which prostratin antagonizes HIV latency highlighting a central role for the action of NF-kappaB.
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PMID:Prostratin antagonizes HIV latency by activating NF-kappaB. 1528 45


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