Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell lines and tumors with defined genetic alterations provide ideal systems in which to test the molecular mechanisms of tumor sensitivity to pathway-targeted therapy. We have generated mouse ovarian epithelial tumor cell lines that contain various combinations of genetic alterations in the p53, c-myc, K-ras and Akt genes. Using both in vitro and in vivo approaches, we investigated the effect of rapamycin on cell proliferation, tumor growth, and the accumulation of peritoneal ascites. We demonstrated that rapamycin effectively inhibits the growth of tumors that rely on Akt signaling for proliferation, whereas tumors in which Akt signaling is not the driving force in proliferation are resistant to rapamycin. The introduction of activated Akt to the rapamycin-resistant cells does not render the cells susceptible to rapamycin if they can use alternative pathways for survival and proliferation. Accordingly, the rapamycin-sensitive tumors develop resistance to rapamycin when presented with alternative survival pathways, such as the mitogen-activated extracellular kinase signaling pathway. The combination of rapamycin and the mitogen-activated extracellular kinase inhibitor PD98059 is required to diminish proliferation in these cell lines. Our results indicate that mammalian target of rapamycin inhibitors may be effective in a subset of tumors that depend on Akt activity for survival but not effective in all tumors that exhibit Akt activation. Tumors with alternative survival pathways may require the inactivation of multiple individual pathways for successful treatment.
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PMID:A genetically defined mouse ovarian carcinoma model for the molecular characterization of pathway-targeted therapy and tumor resistance. 1586 May 81

75 cases of simple, cellular and mitotically active leiomyoma (LM) were studied immunohistochemically with the use of monoclonal antibodies against bcl-2 ("DAKO", 1:80), bax ("Calbiochem, 1:80), c-myc ("Novocastra", 1:100), CD 95 ("Dianova, 1:50), Ki67 ("Dianova", 1:40), PCNA ("Novacastra", 1:100). Apoptosis was assessed by the Tunnel method (ENZO Apop Detek Cell Death Assay System). Simple LM is characterized by apoptosis domination over proliferation in leiomyocytes. Size increase of such a tumor is probably the result of hypertrophy of leiomyocytes and stromal elements proliferation as well as secondary changes. Cellular LM is characterized by about similar level of tumor cell proliferation and apoptosis. Size increase of cellular LM is related to hypertrophy and leiomyocytes number increase probably due to their life lengthening. Mitotically active LM is characterized by domination of proliferation over apoptosis of tumor cells this being main condition of this tumor growth. Various types of LM differ by their stroma composition: fibrocyte prevailing in a simple LM, angiogenesis in mitotically active LM. Combination of adenomyosis with endometrium hyperplasia results in enhancement of proliferation and apoptosis of tumor cells.
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PMID:[Correlation between proliferation and apoptosis in different histological types of uterine leiomyoma]. 1620 96

Androgen receptor (AR) interacts with beta-catenin and can suppress its coactivation of T cell factor 4 (Tcf4) in prostate cancer (PCa) cells. Pin1 is a peptidyl-prolyl cis/trans isomerase that stabilizes beta-catenin by inhibiting its binding to the adenomatous polyposis coli gene product and subsequent glycogen synthase kinase 3beta (GSK-3beta)-dependent degradation. Higher Pin1 expression in primary PCa is correlated with disease recurrence, and this study found that Pin1 expression was markedly increased in metastatic PCa. Consistent with this result, increased expression of Pin1 in transfected LNCaP PCa cells strongly accelerated tumor growth in vivo in immunodeficient mice. Pin1 expression in LNCaP cells enhanced beta-catenin/Tcf4 transcriptional activity, as assessed using Tcf4-regulated reporter genes, and increased expression of endogenous Tcf4 and c-myc. However, in contrast to results in cells with intact PTEN and active GSK-3beta, Pin1 expression in LNCaP PCa cells, which are PTEN deficient, did not increase beta-catenin. Instead, Pin1 expression markedly inhibited the beta-catenin interaction with AR, and Pin1 abrogated the ability of AR to antagonize beta-catenin/Tcf4 binding and transcriptional activity. These findings demonstrate that AR can suppress beta-catenin signaling, that the AR-beta-catenin interaction can be regulated by Pin1, and that abrogation of this interaction can enhance beta-catenin/Tcf4 signaling and contribute to aggressive biological behavior in PCa.
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PMID:Activation of beta-catenin signaling in prostate cancer by peptidyl-prolyl isomerase Pin1-mediated abrogation of the androgen receptor-beta-catenin interaction. 1642 47

Recent reports have indicated that honokiol can induce apoptosis, suppress tumor growth, and inhibit angiogenesis. In this report, we found that honokiol potentiated the apoptosis induced by tumor necrosis factor (TNF) and chemotherapeutic agents, suppressed TNF-induced tumor cell invasion, and inhibited RANKL-induced osteoclastogenesis, all of which are known to require nuclear factor-kappaB (NF-kappaB) activation. Honokiol suppressed NF-kappaB activation induced by a variety of inflammatory stimuli, and this suppression was not cell type specific. Further studies showed that honokiol blocked TNF-induced phosphorylation, ubiquitination, and degradation of IkappaBalpha through the inhibition of activation of IkappaBalpha kinase and of Akt. This led to suppression of the phosphorylation and nuclear translocation of p65 and NF-kappaB-dependent reporter gene expression. Magnolol, a honokiol isomer, was equally active. The expression of NF-kappaB-regulated gene products involved in antiapoptosis (IAP1, IAP2, Bcl-x(L), Bcl-2, cFLIP, TRAF1, and survivin), proliferation (cyclin D1, cyclooxygenase-2, and c-myc), invasion (matrix metalloproteinase-9 and intercellular adhesion molecule-1), and angiogenesis (vascular endothelial growth factor) were also down-regulated by honokiol. Honokiol also down-regulated NF-kappaB activation in in vivo mouse dorsal skin model. Thus, overall, our results indicate that NF-kappaB and NF-kappaB-regulated gene expression inhibited by honokiol enhances apoptosis and suppresses osteoclastogenesis and invasion.
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PMID:Honokiol potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through modulation of nuclear factor-kappaB activation pathway. 1696 32

In Burkitt's lymphoma (BL) cells due to a t(8;14) chromosomal translocation c-myc is often placed in proximity to the Emu enhancer of the Ig locus and upregulated. We demonstrated that in BL cells a peptide nucleic acid (PNA), complementary to intronic Emu sequences (PNAEmuwt), specifically blocks the expression of the c-myc oncogene under the Emu enhancer control and inhibits BL cell growth in culture. Here, we investigated whether PNAEmuwt was also able to block tumor growth in SCID mice inoculated with human BL cell lines. After subcutaneous inoculum in mice BL cells reproducibly form tumors. Both pre-treatment of BL cells with PNAEmuwt before inoculum and chronic intravenous administration of PNAEmuwt to mice already inoculated with BL cells selectively caused increased latency of tumor appearance and decreased final tumor size. Tumors from PNAEmuwt-treated animals showed substantial areas of cell necrosis and of c-myc downregulation. Inhibition of tumor growth was specific and was not observed with PNAEmumut carrying sequence mutations and in BL cell lines where the translocated c-myc is not under the control of the Emu enhancer. These data confirm the potential therapeutic value of PNA targeted to regulatory non-coding regions.
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PMID:Inhibition of Burkitt's lymphoma cells growth in SCID mice by a PNA specific for a regulatory sequence of the translocated c-myc. 1705 16

IFNs have been ascribed to mediate antitumor effects. IFN regulatory factor-1 (IRF-1) is a major target gene of IFNs. It inhibits cell proliferation and oncogenic transformation. Here, we show that 60% of all mRNAs deregulated by oncogenic transformation mediated by c-myc and H-ras are reverted to the expression levels of nontransformed cells by IRF-1. These include cell cycle-regulating genes. An indirect target is cyclin D1. Activation of IRF-1 decreased cyclin D1 expression and cyclin-dependent kinase 4 kinase activity concomitant with change in the levels of hyperphosphorylated retinoblastoma protein. These effects are mediated by inhibition of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathway and a transcriptional repression of cyclin D1. As shown by in vitro assays and tumor growth in nude mice, IRF-1-mediated effects on cell cycle progression were found to be overridden by ectopic expression of cyclin D1. Conversely, decrease of cyclin D1 by RNA interference experiments prevents transformation and tumor growth. The data show that cyclin D1 is a key target for IRF-1-mediated tumor-suppressive effects.
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PMID:Tumor suppression by IFN regulatory factor-1 is mediated by transcriptional down-regulation of cyclin D1. 1740 3

Transcription factor Ying Yang 1 (YY1) indirectly regulates the C promoter-binding factor 1 (CBF1)-dependent Notch1 signaling via direct interaction with the Notch1 receptor intracellular domain (N1IC) on CBF1-response elements. To evaluate the possibility that the N1IC might modulate the gene expression of YY1 target genes through associating with YY1 on the YY1-response elements, we herein investigated the effect of Notch1 signaling on the expression of YY1 target genes. We found that the N1IC bound to the double-stranded oligonucleotides of YY1-response element to activate luciferase activity of the reporter gene with YY1-response elements through a CBF1-independent manner. Furthermore, the N1IC also bound to the promoter of human c-myc oncogene, a YY1 target gene, to elevate c-myc expression via a CBF1-independent pathway. The activation of reporter genes with YY1-response elements or human c-myc promoter by N1IC depended on the formation of N1IC-YY1-associated complex. To delineate the role of the Notch signal pathway in tumorigenesis, K562 cell lines expressing the N1IC were established. Compared with control cells, the proliferation and the tumor growth of N1IC-expressing K562 cells were suppressed. Taken together, these results suggest that the N1IC enhances the human c-myc promoter activity that is partially modulated by YY1 through a CBF1-independent pathway. However, the enhancement of c-myc expression by N1IC is insufficient to promote the tumor growth of K562 cells.
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PMID:The CBF1-independent Notch1 signal pathway activates human c-myc expression partially via transcription factor YY1. 1743 29

The present study aims to evaluate the antigenicity of a PNA complementary to the Emu sequence (PNAEmu) with cancer therapeutic potential properties in Burkitt's lymphoma (BL). In BL cells, the c-myc oncogene is repositioned next to the Emu enhancer of the immunoglobulin (Ig) locus, due to chromosomal translocation, and up-regulated. PNAEmu linked to a nuclear localization signal peptide was shown specifically to block c-myc hyperexpression by inhibiting cell growth in vitro and in vivo. Recently, we reported that the administration of PNAEmu to mice, following inoculation with BL cells, hinders tumor growth without toxic effects. To investigate the potential use of PNAEmu in clinical applications further, we tested its antigenicity. Mice were inoculated with an emulsion of free PNA or PNA crosslinked to the immunogenic carrier keyhole limpet hemocyanin (KLH) with Freund's adjuvant. Antibodies to free PNA were undetected, whereas both IgG and IgM antibodies to PNA-KLH were detected in mouse serum 28 and 38 days after inoculation.
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PMID:The peptide nucleic acid targeted to a regulatory sequence of the translocated c-myc oncogene in Burkitt's lymphoma lacks immunogenicity: follow-up characterization of PNAEmu-NLS. 1746 71

Lung cancer evolves in a multistep process, and its early detection portends a better prognosis. Bronchial washings/brushings and fine-needle aspirations are often used as early screening and cytological diagnosis of lung cancer. In some cases, it is difficult to differentiate morphologically malignant from reactive cells. Epidermal growth factor receptor (EGFR) is a transmembrane receptor overexpressed in high percentage lung cancers, and contributes to tumor growth. Assessing EGFR expression levels by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) may provide critical information of tumor marker abnormalities, assist in the cytological diagnosis, and stratify patients for EGFR inhibitor therapy. Fifty patients with bronchial washings/brushings or fine-needle aspiration specimens, and corresponding histologically confirmed lung biopsies, were studied for EGFR expression with FISH and IHC. Copy numbers of the EGFR gene locus were analyzed with those of chromosome 7 by FISH. EGFR and FISH results were compared to our FISH data with combined EGFR, c-myc, 5p15.2, and chromosome 6 probes in selected cases. Cell blocks, if available, and tissue biopsy sections were used for EGFR IHC. The intensity of IHC was scored, and quantified. Only balanced aneuploidy of EGFR was identified by FISH. Gene amplification was not detected. The chromosomal abnormalities of EGFR were often accompanied by other chromosomal aneuploidies demonstrated in c-myc (8q24), 5p15.2 or 6p, indicating a general genomic instability. About half of the specimens with confirmed malignancy showed EGFR balanced aneuploidy by FISH, and gene copy number was not coupled with protein expression in many cases. The benign or reactive cytology specimens confirmed by biopsies had high specificity by FISH (96%) and IHC (88%). FISH and IHC analysis of EGFR, possibly along with other tumor markers, may be a useful ancillary tool to classify difficult cytology cases and inform clinicians arranging targeted chemotherapy.
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PMID:EGFR expression as an ancillary tool for diagnosing lung cancer in cytology specimens. 1764 93

Knockdown of c-myc expression via RNAi is expected to be an efficient approach to suppress tumor growth. In our preliminary study, we intraperitoneally injected different doses of c-myc-directed esiRNA (esic-MYC, c-myc-directed Escherichia coli expressed and enzyme digested siRNA) into C57BL6/6J mice with bearing B16 melanoma to investigate the inhibitory effect of esic-MYC on tumor growth. However, in high dose esic-MYC treatment groups, the tumor growth inhibition was less efficient than that of low dose treatment groups. Considering the negative regulation roles of eri-1 and adar-1 genes in RNA interference, we downregulated either/both of the two genes with c-myc gene by RNAi. Our results showed esiMERI-1 (esiRNA of mouse eri-1 gene) and esiMADAR-1 (esiRNA of mouse adar-1 gene) could rescue the tumor growth suppression in the high dose esic-MYC treatment groups obviously. The data strongly suggest that silencing of eri-1 and adar-1 homologs of human being should be concerned for cancer therapy by RNAi approach.
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PMID:esiRNA to eri-1 and adar-1 genes improving high doses of c-myc-directed esiRNA effect on mouse melanoma growth inhibition. 1765 62


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