Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-phase kinase associated protein (Skp) 2 is an F-box protein required for substrate recognition of the SCF(Skp2) ubiquitin ligase complex. Skp2 is often overexpressed in transformed cells and in various types of tumors. Downregulation or inhibition of Skp2 inhibits growth of breast cancer cells and small-cell lung carcinoma cells. We downregulated Skp2 in T98G glioblastoma cells using small interfering RNA (siRNA). Downregulation induced p27 and caused growth arrest and apoptosis. Downregulation of both Skp2 and p27 increased apoptosis synergistically. Cyclin E levels and cyclin E-CDK2 kinase activity increased dramatically when both Skp2 and p27 were downregulated. Coincidently, Bcl-2 but not Bcl-xL expression decreased, and caspase-3 was activated. Inhibition of cyclin E-CDK2 kinase activity by forced expression of p21 reversed these effects. Moreover, stable expression of Bcl-2 also abrogated apoptosis induced by downregulation of Skp2 and p27. We suggest that Skp2 in tumor cells suppresses apoptosis through Bcl-2 expression, potentially through regulation of cyclin E-CDK2 activity.
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PMID:Downregulation of Skp2 and p27/Kip1 synergistically induces apoptosis in T98G glioblastoma cells. 1560 73

We previously demonstrated increased numbers of CD34(+) progenitor cells in the peripheral blood of tumor bearers. Also demonstrated was the feasibility of chemoattracting these cells by sponge implants containing VEGF. The present study used a murine Lewis lung carcinoma (LLC) model to test if CD34(+) cells that are chemoattracted to a tumor excision site can be differentiated in situ into dendritic cells and whether this leads to increased local immune reactivity. After surgically excising established LLC tumors, mice received at the excision site gelatin sponge implants containing VEGF to chemoattract CD34(+) cells, and/or GM-CSF plus SCF to induce CD34(+) cell differentiation into dendritic cells. In some studies, lysates of GFP-transfected LLC cells (LLC(GFP)) were also included in the implants as a source of tumor antigen. After 2 weeks, implants and local lymph nodes were removed and analyzed. Implants containing VEGF, GM-CSF/SCF or VEGF/GM-CSF/SCF had a higher proportion of CD34(+) cells compared to control implants. However, the number of dendritic cells was higher in implants containing GM-CSF/SCF or VEGF/GM-CSF/SCF than those containing either VEGF or diluent. Regional lymph node from mice containing GM-CSF/SCF or VEGF/GM-CSF/SCF implants showed increased dendritic cell levels. However, when lysates from LLC(GFP) were added to the implants, the highest proportion of dendritic cells associated with GFP was in lymph nodes of mice containing GM-CSF/SCF implants. Lymph node cells from mice with GM-CSF/SCF or VEGF/GM-CSF/SCF had a higher level of proliferation and IFN-gamma secretion in response to in vitro LLC lysate challenge, with the greatest response being from lymph node cells of mice with GM-CSF/SCF implants. These results suggest the feasibility of using GM-CSF/SCF-containing implants to increase dendritic cell levels, uptake of tumor antigens, trafficking to lymph nodes and stimulation of immune reactivity at tumor excision sites with residual tumor.
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PMID:Cytokine-containing gelfoam implants at a postsurgical tumor excision site to stimulate local immune reactivity. 1645 Mar 95

E7080 is an orally active inhibitor of multiple receptor tyrosine kinases including VEGF, FGF and SCF receptors. In this study, we show the inhibitory activity of E7080 against SCF-induced angiogenesis in vitro and tumor growth of SCF-producing human small cell lung carcinoma H146 cells in vivo. E7080 inhibits SCF-driven tube formation of HUVEC, which express SCF receptor, KIT at the IC(50) value of 5.2 nM and it was almost identical for VEGF-driven one (IC(50) = 5.1 nM). To assess the role of SCF/KIT signaling in tumor angiogenesis, we evaluated the effect of imatinib, a selective KIT kinase inhibitor, on tumor growth of H146 cells in nude mice. Imatinib did not show the potent antitumor activity in vitro (IC(50) = 2,200 nM), because H146 cells did not express KIT. However, oral administration of imatinib at 160 mg/kg clearly slowed tumor growth of H146 cells in nude mice, accompanied by decreased microvessel density. Oral administration of E7080 inhibited tumor growth of H146 cells at doses of 30 and 100 mg/kg in a dose-dependent manner and caused tumor regression at 100 mg/kg. While anti-VEGF antibody also slowed tumor growth, it did not cause tumor regression. These results indicate that KIT signaling has a role in tumor angiogenesis of SCF-producing H146 cells, and E7080 causes regression of H146 tumors as a result of antiangiogenic activity mediated by inhibition of both KIT and VEGF receptor signaling. E7080 may provide therapeutic benefits in the treatment of SCF-producing tumors.
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PMID:E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. 1794 26

Dysregulated behavior of cell cycle proteins and their control by ubiquitin E3 ligases is an emerging theme in human lung cancer. Here, we identified and characterized the activity of a novel F-box protein, termed FBXL2, belonging to the SCF (Skip-Cullin1-F-box protein) E3 ligase family. Ectopically expressed FBXL2 triggered G2/M-phase arrest, induced chromosomal anomalies and increased apoptosis of transformed lung epithelia by mediating polyubiquitination and degradation of the mitotic regulator, cyclin D3. Unlike other F-box proteins that target phosphodegrons within substrates, FBXL2 uniquely recognizes a canonical calmodulin (CaM)-binding motif within cyclin D3 to facilitate its polyubiquitination. CaM bound and protected cyclin D3 from FBXL2 by direct intermolecular competition with the F-box protein for access within this motif. The chemotherapeutic agent vinorelbine increased apoptosis of human lung carcinoma cells by inducing FBXL2 expression and cyclin D3 degradation, an effect accentuated by CaM knockdown. Depletion of endogenous FBXL2 stabilized cyclin D3 levels, accelerated cancer cell growth and increased cell viability after vinorelbine treatment. Last, ectopic expression of FBXL2 significantly inhibited the growth and migration of tumorogenic cells and tumor formation in athymic nude mice. These observations implicate SCF(FBXL2) as an indispensible regulator of mitosis that serves as a tumor suppressor.
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PMID:F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest. 2202 Mar 28

The serine/threonine kinase Akt plays a central role in cell proliferation, survival and metabolism, and its hyperactivation is linked to cancer progression. Here we report that Akt undergoes K64 methylation by SETDB1, which is crucial for cell membrane recruitment, phosphorylation and activation of Akt following growth factor stimulation. Furthermore, we reveal an adaptor function of histone demethylase JMJD2A, which is important for recognizing Akt K64 methylation and recruits E3 ligase TRAF6 and Skp2-SCF to the Akt complex, independently of its demethylase activity, thereby initiating K63-linked ubiquitination, cell membrane recruitment and activation of Akt. Notably, the cancer-associated Akt mutant E17K displays enhanced K64 methylation, leading to its hyper-phosphorylation and activation. SETDB1-mediated Akt K64 methylation is upregulated and correlated with Akt hyperactivation in non-small-cell lung carcinoma (NSCLC), promotes tumour development and predicts poor outcome. Collectively, these findings reveal complicated layers of Akt activation regulation coordinated by SETDB1-mediated Akt K64 methylation to drive tumorigenesis.
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PMID:SETDB1-mediated methylation of Akt promotes its K63-linked ubiquitination and activation leading to tumorigenesis. 3069 24