Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Decreased expression of p16 may result from hypermethylation of the promoter or from deletion of the gene. It can lead to intensified proliferation of neoplastic cells and to cytostatic drug resistance. The study was aimed at the examination of prognostic value of p16 expression in relation to Ki67 and caspase-3 in ovarian cancers using immunohistochemistry. The immunohistochemical studies were performed on 73 paraffin-embedded samples of ovarian cancers from 43 patients and samples from 6 healthy ovaries. We have used monoclonal antibodies against p16. ABC method and DAB were used for antigens visualisation. The intensity of the immunohistochemical reactions was appraised using the semi-quantitative IRS scale. In healthy ovaries we have shown strong reaction in the nuclei of surface epithelium. In the case of studied ovarian cancers, the reaction of a nuclear and cytoplasmic localization was obtained. The mean overall immunoreactivity score of nuclear p16 expression amounted to 5.30+/-3.44 SD in primary laparotomy material and 6.61+/-4.34 SD in secondary cytoreduction material. Statistical analysis demonstrated that lower p16 expression was typical of the younger patients and the patients who died. Kaplan-Meier's analysis proved that lower expression of p16 was characteristic of cases with shorter overall survival. In the present study we have demonstrated that lowered p16 expression represented an unfavourable prognostic index in ovarian cancer. Lowered p16 expression was also typical for chemotherapy-resistant ceases (cases of lower caspase-3 and higher Ki67 at secondary cytoreduction expression).
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PMID:Decreased expression of p16 in ovarian cancers represents an unfavourable prognostic factor. 1828 37

2-Methoxyestradiol (2-ME) has been found to possess antitumor activity in vivo and in vitro. It has been suggested that 2-ME induces apoptosis resulting in G2/M arrest of tumor cells. In this study, the effect of 2-ME was evaluated in rat osteosarcoma and malignant fibrous histiocytoma (MFH) cell lines. 2-ME was used at final concentrations of 100 nM to 2 microM. The effect of 2-ME on cell growth was measured by the MTS assay. Induction of apoptosis and activation of caspase-3 were investigated along with apoptosis-related gene expression. The data showed that 2-ME significantly inhibited cell growth, inducing apoptosis. The activity of caspase-3 was increased at 20 h and 40 h in both cell lines. 2-ME induced p16 expression, which was possibly involved in the apoptotic process. These results suggested that the 2-ME-induced apoptosis of rat osteosarcoma and rat MFH cells was accompanied by caspase-3 activation through p16 induction.
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PMID:Growth inhibition and induction of apoptosis by 2-methoxyestradiol in rat osteosarcoma and malignant fibrous histiocytoma cell lines. 1839 77

Gynostemma pentaphyllum Makino is known in Asia for its effect on the treatment of hepatitis and cardiovascular diseases. Gypenosides (Gyp) are the major components extracted from Gynostemma pentaphyllum Makino. However, the molecular mechanism underlying the Gyp-induced cell cycle arrest and apoptotic process is unclear. In this study, the chemopreventive role of Gyp in human lung cancer (A549) cells in vitro was evaluated by studying the regulation of the cell cycle and apoptosis. Gyp induced GO/G1 arrest and apoptosis in the human lung cancer A549 cells. Investigation of the cyclin-dependent protein kinase inhibitors by Western blotting showed that p16, p21, p27 and p53 proteins were increased with the increasing time of incubation with Gyp in the A549 cells. This increase may be the major factor by which Gyp caused GO/G1 arrest in the examined cells. Flow cytometric assay and gel electrophoresis of DNA fragmentation also confirmed that Gyp induced apoptosis in the A549 cells. Our data demonstrated that Gyp-induced apoptotic cell death was accompanied by up-regulation of Bax, caspase-3 and caspase-9, but down-regulation of the Bcl-2 levels. Taken together, Gyp appears to exert its anticancer properties by inducing GO/GI-phase arrest and apoptosis via activation of caspase-3 in human lung A549 cancer cells.
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PMID:Gypenosides induced G0/G1 arrest via inhibition of cyclin E and induction of apoptosis via activation of caspases-3 and -9 in human lung cancer A-549 cells. 1846 6

Targeted therapies directed against individual cancer-specific molecular alterations offer the development of disease-specific and individualized treatment strategies. Activation of the transcription factor E2F-1 via alteration of the p16-cyclinD-Rb pathway is one of the key molecular events in the development of gliomas. E2F-1 binds to and activates the E2F-1 promoter in an autoregulatory manner. The human E2F-1 promoter has been shown to be selectively activated in tumor cells with a defect in the pRb pathway. Paradoxically, E2F-1 also carries tumor suppressor function. Our investigations focused on analyzing the dynamics of the activity of the E2F-1 responsive element under basal conditions and certain stimuli such as chemotherapy using molecular imaging technology. We constructed a retrovirus bearing the Cis-E2F-TA-LITG reporter system to noninvasively assess E2F-1-dependent transcriptional regulation in culture and in vivo. We show that our reporter system is sensitive to monitor various changes in cellular E2F-1 levels and its transcriptional control of our reporter system to follow the state of the Rb/E2F pathway and the DNA damage-induced up-regulation of E2F-1 activity in vivo. Exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea leads to increased E2F-1 expression levels in a dose- and time-dependent manner, which can be quantified by imaging in vivo, leading to an alteration of cell cycle progression and caspase 3/7 activity. In summary, noninvasive imaging of E2F-1 as a common downstream regulator of cell cycle progression using the Cis-E2F-TA-LUC-IRES-TKGFP reporter system is highly attractive for evaluating the kinetics of cell cycle regulation and the effects of novel cell cycle targeting anticancer agents in vivo.
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PMID:Noninvasive assessment of E2F-1-mediated transcriptional regulation in vivo. 1863 48

Transforming growth factor-beta (TGF-beta)-Smad signaling pathway participates in the regulation of a variety of cellular activities. Unlike the high incidences of Smad4 mutation or deletion in pancreatic cancer and gastrointestinal cancers, Smad4 gene is seldom mutated or deleted in hepatocellular carcinoma (HCC). The role of TGF-beta-Smad4 signaling pathway in leading to carcinogenesis of liver cells remains unknown. In this study, we succeeded in silencing Smad4 using lentiviral-mediated Smad4 RNA interference (RNAi). We investigated the role of Smad4 in TGF-beta1-induced cell proliferation and apoptosis of HCC cell line SMMC-7721. We determined cell proliferation, apoptosis, and expression of p21, p16, p53 and caspase 3. Results showed that TGF-beta1 not only had a significant anti-proliferation effect but also induced cellular apoptosis in SMMC-7721 cells. These effects induced by TGF-beta1 were almost completely blocked by the knockdown of Smad4. Western blot analysis revealed that p16 was up-regulated and caspase 3 was activated by silencing of Smad4, and the expression of p21 and wild-type p53 were not affected. These results suggest that TGF-beta1-induced cell growth inhibition by up-regulating p16 expression and cellular apoptosis by activating caspase 3 was Smad4-dependent. Additionally, the knock down of a specific gene using lentiviral-mediated RNAi appears to be a promising tool and strategy for analyzing endogenous gene function.
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PMID:Lentiviral-mediated Smad4 RNAi induced anti-proliferation by p16 up-regulation and apoptosis by caspase 3 down-regulation in hepatoma SMMC-7721 cells. 1894 1

The transcriptional regulator TBX2 is genetically amplified in several cancers and has, in addition, important roles in development. In carcinogenesis, TBX2 regulates the cell cycle by suppressing the expression of cyclin-dependent kinase (CDK) inhibitors and destabilizes p53 by suppressing expression of ARF. In embryogenesis, however, TBX2 appears to act independently of the cell cycle or p53 and is regulated by growth factors. Tumorigenic functions of TBX2 that are independent of p53 or cell cycle regulation remain poorly understood. Here we used SW13 carcinoma cells which express inactive p53 and have no detectable p16 or p21 CDK-inhibitors as a model to study these functions. Expression of TBX2 in SW13 cells had no effect on the cell cycle but promoted anchorage-independence and increased resistance to apoptotic stimuli including UV-irradiation, the cytotoxic drug doxorubicin and lethal endoplasmic-reticulum stress. This is a cell type-dependent effect as TBX2 overexpression in PANC1 pancreatic cancer cells which are p53-negative has no effect on colony formation or survival after irradiation. Mechanistically, in SW13 cells, TBX2 overexpression strongly reduced the activation of caspase 3, 8 and 9 following UV-irradiation but without altering the expression of the corresponding procaspases. There were, however, dramatic and specific decreases in the expression of procaspases 1 and 4. The expression of the inhibitor of apoptosis, cIAP2/BIRC3, increased in TBX2-overexpressing cells. TBX2 was upregulated in a PI3K-dependent manner by growth factors that are tumorigenic for SW13. Inhibition of Akt phosphorylation abrogates upregulation of TBX2 by FGF-4. Our findings identify TBX2 as a cell type-dependent survival factor under a p53-negative background, and are indicative of a potentially wider role for TBX2 in carcinogenesis than hitherto described.
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PMID:Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma. 1921 23

Vulvar carcinoma is a rare female genital neoplasia. Radical surgery, which has been the standard treatment approach, is often accompanied by considerable morbidity. To reduce the incidence of complications there has been a movement toward individualised therapy and less radical surgery. Associated with this, new tumour markers that could serve as prognostic indicators would be of considerable value to guide treatment decision. In this review, a brief update of molecular pathological markers of vulvar carcinomas is provided, and their impact as prognostic markers is addressed. p16, p21, p14, p27, cyclin A, cyclin D1, p53, vascular endothelial growth factor (VEGF), transforming growth factor alpha, HER-2 and epidermal growth factor receptor (EGFR) have been found to be important in the pathogenesis and/or progression of vulvar carcinomas. Furthermore, human papillomavirus, p16, p21, p14, p53, VEGF, CD44v3, CD44v6, CD44v4, CD44v9, CD44v10, HER-2, EGFR, matrix metalloproteinase-12, caspase 3, Bcl-2 and nm23-H1 have been correlated to clinical outcome of patients with vulvar carcinomas. However, due to the relative small number of studies reported for each molecular pathological marker, and the relative small number of vulvar carcinomas included and the lack of multivariate analysis in the majority of these studies, no conclusion regarding the prognostic value of these markers can be drawn. Therefore, the investigated markers have not yet earned a place in standard clinical diagnostics or treatment, and further studies are needed to clarify the clinical value of these markers.
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PMID:A review of molecular pathological markers in vulvar carcinoma: lack of application in clinical practice. 1925 52

Despite advances in screening and treatment, colorectal cancer remains the second leading cause of cancer-related death in the United States. Cyclin-dependent kinases (Cdk) are deregulated in colorectal cancer by silencing of the Cdk inhibitor p16(Ink4a) and other mechanisms. We tested whether the small molecule Cdk inhibitor SNS-032 (formerly BMS-387032), which targets Cdk2, Cdk7, and Cdk9, can prevent intestinal tumorigenesis in mouse models. We generated mice with high intestinal tumor loads by combining the multiple intestinal neoplasia (Min) mutation with Ink4a/Arf mutations and inducing colitis with dextran sulfate sodium. p16-null Min mice (n = 17) began dextran sulfate sodium treatment at week 5 and i.p. injection of carrier or SNS-032 at week 6. Mice were sacrificed at week 12. SNS-032 was well tolerated and reduced colon tumor burden to 36% of that in carrier-treated mice (P < 0.001). We then extended the study to Ink4/Arf-null Min mice (n = 14) and increased the drug dose frequency. SNS-032 treatment reduced the intestinal tumor number to 25% and intestinal tumor burden to 16% of carrier-treated mice (P < 0.0001). DNA synthesis in non-neoplastic and tumor epithelial cells, detected by bromodeoxyuridine incorporation, was modestly reduced by acute SNS-032 treatment. The mitotic index, detected by histone H3 phosphorylation, was distinctly decreased (P < 0.03), and apoptosis, detected by caspase 3 activation, was increased (P < 0.005). These results show the chemoprevention of intestinal tumorigenesis by SNS-032. Our findings support further study of Cdk inhibitors for chemoprevention and therapy of colon cancer.
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PMID:Chemoprevention of mouse intestinal tumorigenesis by the cyclin-dependent kinase inhibitor SNS-032. 1972 96

This study evaluated the in vivo antitumor activity of grape-derived polyphenols. BALB/c mice were subcutaneously implanted with C26 colon carcinoma cells, and 2 d later they received either solvent or red wine polyphenols (RWPs) (100 mg/kg/d, human equivalent dose approximately 500 mg/d) in the drinking water for 25 d. Wistar rats received either solvent or RWPs (100 mg/kg/d, human equivalent dose approximately 1000 mg/d) in the drinking water 1 wk before injection of azoxymethane and were studied 10 wk later. In mice, RWPs inhibited tumor growth by 31%, reduced tumor vascularization and the number of lung metastases, decreased proliferation as indicated by down-regulation of Ki67, cyclin D1, and UHRF1, and increased apoptosis as indicated by TUNEL staining and active caspase-3 levels in tumor cells. RWPs reduced expression of VEGF, matrix metalloproteinase (MMP)-2, MMP-9, and cyclooxygenase-2 and increased expression of tumor suppressor genes p16(INK4A), p53, and p73 in tumor cells. In rats, RWPs reduced by 49% the number of azoxymethane-induced aberrant crypt foci (preneoplastic lesions) in colon. Thus, RWPs effectively reduced the development of colon carcinoma tumors in vivo by blunting tumor vascularization and by inhibiting proliferation and promoting apoptosis of tumor cells subsequent to an up-regulation of tumor suppressor genes.
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PMID:Intake of grape-derived polyphenols reduces C26 tumor growth by inhibiting angiogenesis and inducing apoptosis. 2044 18

Curcumin has been verified as an anti-cancer compound via multiple molecular targets. Its effective mechanisms include cell cycle arrest, inducing apoptosis, suppressing oncogenes, and enhancing tumor suppressor genes. The resistance of cells to chemotherapy, however, derives from the variable genetic aberration of cancer cells. Consequently, the core signaling pathways of glioblastoma have been explored to evaluate the efficacy of curcumin in proceeding through mutated genes in those pathways. In this study, the efficacy of curcumin was investigated in DBTRG cells. The cytotoxic ability was detected with MTT assay, and the influence of the cell cycle was checked with flow cytometry. The influence of the core signaling pathways was evaluated by Western blotting through the predominantly mutated proteins which included p53, p21, and cdc2 in the p53 pathway, CDKN2A/p16 and RB in the RB pathway, and EGFR, mTOR, Ras, PTEN, and Akt in the RTK-Ras-PI3K pathway. In addition, the apoptotic effect was determined by apoptosis-associated proteins Bcl-2, Bax, and caspase 3. Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay. In the core signaling pathways of glioblastoma, curcumin either significantly influences the p53 pathway by enhancing p53 and p21 and suppressing cdc2 or significantly inhibits the RB pathway by enhancing CDKN2A/p16 and suppressing phosphorylated RB. In the apoptotic pathway, the Bax and caspase 3 are significantly suppressed by curcumin and the Giemsa stain elucidates apoptotic features of DBTRG cells as well. In conclusion, curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway.
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PMID:The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma. 2059 1


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