Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dibenzoylmethane (DBM), a minor beta-diketone constituent of licorice, has been shown to exhibit antineoplastic effects in prostate cancer cell lines by induction of cell cycle arrest and regulation of androgen receptor expression. In the present study, we investigated the in vitro and in vivo efficacy of DBM using TRAMP-C1 cell lines and TRAMP mice. DBM was found to arrest TRAMP-C1 cells at G(2)-M phase of cell cycle and suppressed phosphorylated retinoblastoma, cyclin D1, and cyclin A. Importantly, DBM was found to be equally effective in suppression of prostate tumor progression in TRAMP mice. At 8 or 12 weeks of age, mice were fed control or 1% DBM-supplemented diets until 24 weeks of age. Our results show that DBM-fed groups had a lower incidence of palpable tumor and high-grade prostatic intraepithelial neoplasia. Subsequent mechanistic studies show that the expression of phosphorylated retinoblastoma, c-myc, cyclin D1, cyclin A, phosphorylated Akt, phosphorylated PDK-1, and phosphorylated S6 was significantly reduced by DBM. Our findings suggest that DBM blocks the growth and progression of prostate cancer in TRAMP mice via modulation of tumor cell cycle regulation and therefore merits its consideration for future clinical intervention of human prostate cancer.
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PMID:Dietary feeding of dibenzoylmethane inhibits prostate cancer in transgenic adenocarcinoma of the mouse prostate model. 1970 64

The malignant transformation of breast epithelium involves a number of cellular pathways, including those dependent on signaling from TGF beta. Tranilast [N-(3, 4-dimethoxycinnamonyl)-anthranilic acid] is a drug that is used in Japan to control allergic disorders in patients, and its mechanism of action involves TGF beta. In view of the multiple roles of TGF beta in tumor progression, we hypothesized in this study that tranilast impacts cell proliferation, apoptosis, and migration. Using the mouse breast cancer cell line 4T1, our studies showed that tranilast increases AKT1 phosphorylation and decreases ERK1/2 phosphorylation. Alterations in the cell cycle mediators' cyclin D1, p27, cyclin A, pRB, cyclin B, and Cdc2 were observed after exposure to tranilast, favoring cell arrest beyond the G1/S phase. Tranilast reduced tumor cell proliferation even when it was amplified by exogenous TGF beta. TGF beta-neutralizing antibody did not cause a significant decrease in cell proliferation. Tranilast treatment upregulates p53, induces PARP cleavage in vitro, consistent with a promotion of tumor cell apoptosis. TGF beta-neutralizing antibody downregulates endoglin and matrix metalloproteinases (MMP)-9 levels in vitro indicating that the tranilast effect is mediated through TGF beta modulation. Tranilast treatment results in the inhibition of cell migration and invasion. Western blot analysis of tumor lysates from tranilast-treated mice shows decreased levels of TGF beta1, endoglin, and significantly higher levels of p53 and cleaved PARP. Cleaved caspase 3 expression is significantly elevated in tranilast-treated mouse breast tumors. To conclude, tranilast induces cellular and molecular changes in murine breast cancer that can be exploited in preclinical therapeutic trials.
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PMID:Tranilast inhibits cell proliferation and migration and promotes apoptosis in murine breast cancer. 2014 38

Breast cancer represents the second leading cause of cancer-related deaths in the world. There is increasing evidence that perturbation of cell cycle regulation is an important contributing factor to various cancer progression stages. There are key checkpoints in the cell cycle involving various regulatory proteins. The relationship between these cell cycle regulatory proteins and cell cycle arrest by cyclo-oxygenase (COX) inhibitors during neoplastic progression remains largely unknown. Preclinical studies and epidemiological investigations have consistently shown that non-steroidal anti-inflammatory drugs have some anti-proliferative and anti-oxidative stress response on various tumors. In this study, the effect of etodolac, a 1,8-diethyl-1,3,4,9-tetrahydro-pyrano (3,4-beta) indole-1-acetic acid on signaling pathways was investigated by examining the differential expression of various cell cycle regulatory protein genes. A human cell cycle gene array was used to profile the expression of 96 genes involved in the cell cycle regulation. Differentially expressed genes were highly altered by etodolac treatment. Twenty-six genes were up- and 20 down-regulated with 0.5 and 2 mM etodolac treatment, respectively. Seven genes (ATM, BAX, CCNA2, CDC27, RAD50 and p21) were prominently altered, and six (ATM, CCND2, CCNF, CDC20, CDK1A and RAD50) were commonly altered with both concentrations. This finding indicated that etodolac could play a critical role on cancer cells by inducing cell death.
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PMID:Profiling of cell cycle genes of breast cells exposed to etodolac. 2037 55

Circadian disruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03 pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT) from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling was determined with DNA microarrays at endogenous circadian time (CT) 4 and CT16. Circadian mRNA expression patterns were determined for clock genes Rev-erbalpha, Per2, and Bmal1, cellular stress genes Hspa8 and Cirbp, and cyclin A2 gene Ccna2 in liver and tumor. The 24-hour patterns in telemetered rest-activity and body temperature and plasma corticosterone and insulin-like growth factor-I (IGF-I) were assessed. We showed that MT inhibited cancer growth by approximately 40% as compared with AL (P = 0.011) irrespective of calorie intake. Clock gene transcription remained arrhythmic in tumors irrespective of feeding schedule or diet. Yet, MT upregulated or downregulated the expression of 423 tumor genes, according to CT. Moreover, 36 genes involved in cellular stress, cell cycle, and metabolism were upregulated at one CT and downregulated 12 h apart. MT induced >10-fold circadian expression of Hspa8, Cirbp, and Ccna2 in tumors. Corticosterone or IGF-I patterns played no role in tumor growth inhibition. In contrast, MT consistently doubled the circadian amplitude of body temperature. Peak and trough respectively corresponded to peak expressions of Hspa8 and Cirbp in tumors. The reinforcement of the host circadian timing system with MT induced 24-hour rhythmic expression of critical genes in clock-deficient tumors, which translated into cancer growth inhibition. Targeting circadian clocks represents a novel potential challenge for cancer therapeutics.
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PMID:Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing. 2039 8

The Ras/Raf/MEK/ERK signaling has been implicated in uncontrolled cell proliferation and tumor progression in pancreatic cancer. The purpose of this study is to evaluate the antitumor activity of MEK inhibitor U0126 in combination with Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in pancreatic cancer cells. Western blotting showed that 17-AAG caused a 2- to 3-fold transient activation of MEK/ERK signaling in pancreatic cancer cells. The activation sustained for 6 h before phospho-ERK (p-ERK) destabilization. The selective MEK inhibitor U0126 completely abolished 17-AAG induced ERK1/2 activation and resulted in more than 80% of phospho-ERK degradation after only 15 min treatment. Moreover, U0126 had complementary effect on 17-AAG regulated oncogenic and cell cycle related proteins. Although 17-AAG downregulated cyclin D1, cyclin E, CDK4 and CDK6, it led to cyclin A and CDK2 accumulation, which was reversed by the addition of U0126. Antiproliferation assay showed that combination of U0126 and 17-AAG resulted in synergistic cytotoxic effect. More importantly, 17-AAG alone only exhibited moderate inhibition of cell migration in vitro, while addition of U0126 dramatically enhanced the inhibitory effect by 2- to 5-fold. Taken together, these data demonstrate that MEK inhibitor U0126 potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. The combination of Hsp90 and MEK inhibition could provide a promising avenue for the treatment of pancreatic cancer.
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PMID:MEK inhibition potentiates the activity of Hsp90 inhibitor 17-AAG against pancreatic cancer cells. 2066 73

The polycomb group (PcG) genes encode a family of proteins that methylate and ubiquitinate histones to close chromatin and suppress gene expression. PcG proteins are present at elevated levels in cancer cells, and this is associated with reduced tumor suppressor protein level and enhanced cell survival. Agents that reduce PcG protein level are regarded as potentially cancer-preventative agents. Sulforaphane (SFN) is a biologically important isothiocyanate found in cruciferous vegetables that is an important candidate chemopreventive agent. However, the impact of SFN on the level and function of PcG proteins in skin cancer cells has not been assessed. We show that SFN treatment causes a concentration-dependent reduction in PcG protein (Bmi-1, Ezh2) expression in SCC-13 skin cancer cells and also reduces trimethylation of lysine 27 of histone H3. This is associated with accumulation of cells in G(2)/M phase; reduced levels of cyclin B1, cyclin A, cyclin dependent kinases 1 and 2; and increased p21(Cip1) expression. Sulforaphane treatment also increases cleavage of procaspase 3, 8, and 9 and enhances PARP cleavage and apoptosis. Similar results are observed in other skin-derived cell immortalized and transformed cell lines. Forced expression of the Bmi-1 polycomb protein in SCC-13 cells reverses these effects. The SFN-dependent loss of Bmi-1 and Ezh2 is due to proteasome-associated degradation. These results suggest that dietary isothiocyanates may suppress cancer progression by reducing PcG protein level via a proteasome-dependent mechanism, thereby inhibiting PcG-dependent pro-survival epigenetic events.
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PMID:Sulforaphane suppresses polycomb group protein level via a proteasome-dependent mechanism in skin cancer cells. 2180 89

Nearly half of human cancers harbor p53 mutations, which can promote cancerous growth, metastasis, and resistance to therapy. The gain of function of mutant p53 is partly mediated by its ability to form a complex with NF-Y or p63/p73. Here, we demonstrate that TopBP1 mediates these activities in cancer, and we provide both in vitro and in vivo evidence to support its role. We show that TopBP1 interacts with p53 hot spot mutants and NF-YA and promotes mutant p53 and p300 recruitment to NF-Y target gene promoters. TopBP1 also facilitates mutant p53 interaction with and inhibition of the transcriptional activities of p63/p73. Depletion of TopBP1 in mutant p53 cancer cells leads to downregulation of NF-Y target genes cyclin A and Cdk1 and upregulation of p63/p73 target genes such as Bax and Noxa. Mutant p53-mediated resistance to chemotherapeutic agents depends on TopBP1. The growth-promoting activity of mutant p53 in a xenograft model also requires TopBP1. Thus, TopBP1 mediates mutant p53 gain of function in cancer. Since TopBP1 is often overexpressed in cancer cells and is recruited to cooperate with mutant p53 for tumor progression, TopBP1/mutant p53 interaction may be a new therapeutic target in cancer.
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PMID:TopBP1 mediates mutant p53 gain of function through NF-Y and p63/p73. 2193 Jul 90

Previous studies have shown that the inhibitory effect of betulinic acid (BA) on specificity protein 1 (Sp1) expression is involved in the prevention of cancer progression, but the mechanism of this effect remains to be delineated. In this study, we determined that BA treatment in HeLa cells increased the sumoylation of Sp1 by inhibiting sentrin-specific protease 1 expression. The subsequent recruitment of E3 ubiquitin-protein ligase RING finger protein 4 resulted in ubiquitin-mediated degradation in a 26S-proteosome-dependent pathway. In addition, both BA treatment and mithramycin A (MMA) treatment inhibited lung tumor growth and down-regulated Sp1 protein expression in Kras(G12D)-induced lung cancers of bitransgenic mice. In gene expression profiles of Kras(G12D)-induced lung cancers in bitransgenic mice with and without Sp1 inhibition, 542 genes were affected by MMA treatment. One of the gene products, cyclin A2, which was involved in the S and G(2)/M phase transition during cell cycle progression, was investigated in detail because its expression was regulated by Sp1. The down-regulation of cyclin A2 by BA treatment resulted in decreased retinoblastoma protein phosphorylation and cell cycle G(2)/M arrest. The BA-mediated cellular Sp1 degradation and antitumor effect were also confirmed in a xenograft mouse model by using H1299 cells. The knockdown of Sp1 in lung cancer cells attenuated the tumor-suppressive effect of BA. Taken together, the results of this study clarify the mechanism of BA-mediated Sp1 degradation and identify a pivotal role for Sp1 in the BA-induced repression of lung cancer growth.
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PMID:Betulinic acid decreases specificity protein 1 (Sp1) level via increasing the sumoylation of sp1 to inhibit lung cancer growth. 2295 72

The translationally controlled tumor protein (TCTP) plays a role in cell growth, cell cycle and cancer progression. TCTP controls negatively the stability of the p53 tumor suppressor protein and interacts with the cellular cytoskeleton. The deregulation of the actin and cytokeratin cytoskeleton is responsible for the increased migratory activity of tumor cells and is linked with poor patient outcome. Recent studies indicate that cyclin A,a key regulator of cell cycle, controls actin organization and negatively regulates cell motility via regulation of RhoA expression. We studied the organization of actin and cytokeratin cytoskeleton and the expression of TCTP, p53,cyclin A, RhoA and actin in HIO180 non-transformed ovarian epithelial cells, and OVCAR3 and SKOV3 (expressing low level of inducible p53) ovarian epithelial cancer cells with different metastatic potential. Immunostaining and ultrastructural analyses illustrated a dramatic difference in the organization of the cytokeratin and actin filaments in non-transformed versus cancer cell lines. We also determined that there is an inverse relationship between the level of TCTP/RhoA and actin/p53/cyclin A expression in ovarian cancer cell lines. This previously unidentified negative relationship between TCTP/RhoA and actin/p53/cyclin A may suggest that this interaction is linked with the high aggressiveness of ovarian cancers.
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PMID:Inverse relationship between TCTP/RhoA and p53 /cyclin A/actin expression in ovarian cancer cells. 2304 65

In Barrett's esophagus (BE), the normal squamous lining of the esophagus is replaced by specialized columnar epithelium. Endoscopic surveillance with autofluorescence imaging (AFI) and molecular biomarkers have been studied separately to detect early neoplasia (EN) in BE. The combination of advanced-imaging modalities and biomarkers has not been investigated; AFI may help detecting biomarkers as a risk-stratification tool. We retrospectively evaluated a cohort of patients undergoing endoscopy for EN in BE with AFI and correlated five biomarkers (HPP1, RUNX3, p16, cyclin A, and p53) in tissue samples with AFI and dysplasia status. Fifty-eight samples from a previous prospective study were selected: 15 true-positive (TP: AFI-positive, EN), 21 false-positive (FP: AFI-positive, no EN), 12 true-negative (TN1; AFI-negative, no EN in sample), 10 true-negative (TN2: AFI-negative, no EN in esophagus). Methylation-specific RT-PCR was performed for HPP1, RUNX3, p16, and immunohistochemistry for cyclin A, p53. P < 0.05 was considered statistically significant. Bonferroni correction was used for multiple comparisons. P16, cyclin A, p53 correlated with dysplasia (P < 0.01, P = 0.003, P < 0.001, respectively). Increased p16 methylation was observed between TP versus TN2 (P = 0.003) and TN1 versus TN2 (P = 0.04) subgroups, suggesting a field defect. Only p53 correlated with AFI-status (P = 0.003). After exclusion of EN samples, significance was lost. Although correlation with dysplasia status was confirmed for p16, cyclin A and p53, underlining the importance of these biomarkers as an early event in neoplastic progression, none of the investigated biomarkers correlated with AFI status. A larger prospective study is needed to assess the combination of AFI and a larger panel of biomarkers to improve risk stratification in BE.
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PMID:Endoscopic TriModal imaging and biomarkers for neoplasia conjoined: a feasibility study in Barrett's esophagus. 2306 99


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