Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bladder cancer-associated protein gene (BLCAP) is a novel candidate tumor suppressor gene identified from the human bladder carcinoma. Our previous studies have shown that BLCAP overexpression could inhibit cell growth by inducing apoptosis in HeLa cells [Zuo Z, Zhao M, Liu J, Gao G, Wu X: Tumor Biol 27: 221-226, 2006]. Such evidence suggests the alterations in BLCAP may play an important role in tumorigenesis. To further study the biological function of the BLCAP gene, we constructed a recombinant retroviral vector encoding BLCAP cDNA. Overexpressed BLCAP, via stable infection of exogenous BLCAP, resulted in growth inhibition of the human tongue cancer cell line Tca8113 in vitro, accompanied by S phase cell cycle arrest and apoptosis. The growth inhibition was correlated with up-regulation of p21(WAF1/CIP1 )expression and down-regulation of Bcl-XL and Bcl-2 expressions. However, p53 expression and NF-kappaB activity remained unchanged post infection. Furthermore, no changes in p53 phosphorylation at Ser46 and nuclear localization, which are critical to p53 function, were observed in BLCAP-overexpressed cells. Taken together, BLCAP may play a role not only in regulating cell proliferation but also in coordinating apoptosis and cell cycle via a novel way independent of p53 and NF-kappaB.
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PMID:Overexpression of BLCAP induces S phase arrest and apoptosis independent of p53 and NF-kappaB in human tongue carcinoma : BLCAP overexpression induces S phase arrest and apoptosis. 1703 75

Apigenin, a common dietary flavonoid present in many fruits and vegetables, is a nonmutagenic chemopreventive agent. In the present study, we investigated the effect of apigenin on the radiosensitivity of SQ-5 cells, which are derived from a human lung carcinoma. Actively growing cells were incubated for 16 h at 37 degrees C in medium containing 40 muM apigenin. The cells were then irradiated with X-rays and incubated with apigenin for a further 8 h. Radiosensitivity was assessed using a clonogenic assay. Apoptosis and necrosis were assessed using acridine orange/ethidium bromide double staining. Cells incubated with apigenin exhibited significantly greater radiosensitivity and apoptosis levels than cells not incubated with apigenin. Protein levels were measured by Western blotting. Incubation with apigenin increased protein expression of WAF1/p21 and decreased protein expression of Bcl-2. Furthermore, apigenin sensitized SQ-5 spheroids (cell aggregates growing in a three-dimensional structure that simulate the growth and microenvironmental conditions of in vivo tumors) to radiation. Thus, apigenin appears to be a promising radiosensitizing agent for use against human carcinomas.
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PMID:The chemopreventive flavonoid apigenin confers radiosensitizing effect in human tumor cells grown as monolayers and spheroids. 1713 15

San-Zhong-Kui-Jian-Tang (SZKJT; Japanese name: Sanshu-kaigen-to), a traditional Chinese medicine prescription, has been used for treating patients with various cancers. This study first investigates the anticancer effect of SZKJT in two human breast cancer cell lines, MCF-7 and MDA-MB-231. SZKJT exhibited effective cell growth inhibition by inducing cancer cells to undergo G0/G1 phase arrest and apoptosis. Blockade of cell cycle was associated with increased p21/WAF1 levels, and reduced amounts of cyclinD1, cyclinD2 in a p53-independent manner. SZKJT treatment triggered the mitochondrial apoptotic pathway indicated by changing Bax/Bcl-2 ratios, cytochrome c release and caspase-9 activation, but did not act on Fas/Fas ligand pathways and the activation of caspase-8. Further investigation revealed that SZKJT's inhibition of cell growth effect was also evident in a nude mice model. Taken together, our study suggests that the induction of p21/WAF1 and activity of the mitochondrial apoptotic system may participate in the antiproliferative activity of SZKJY in human breast cancer cells.
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PMID:San-Zhong-Kui-Jian-Tang, a traditional Chinese medicine prescription, inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis. 1714 69

We have recently shown that thymoquinone (TQ) is an antineoplastic drug that induces p53-dependent apoptosis in human colon cancer cells. This study evaluated the antiproliferative and pro-apoptotic effects of TQ in two human osteosarcoma cell lines with different p53 mutation status. TQ decreased cell survival dose-dependently and, more significantly, in p53-null MG63 cells (IC(50) = 17 muM) than in p53-mutant MNNG/HOS cells (IC(50) = 38 muM). Cell viability was reduced more selectively in MG63 tumor cells than in normal human osteoblasts. Flow cytometric analysis showed that TQ induced a much greater increase in the PreG(1) (apoptotic) cell population, but no cell cycle arrest in MG63. G(2)/M arrest in MNNG/HOS cells was associated with p21(WAF1) upregulation. Using three DNA damage assays, TQ was confirmed to result in a significantly greater extent of apoptosis in p53 null MG63 cells. Although the Bax/Bcl-2 ratios were not differentially modulated in both cell lines, the mitochondrial pathway appeared to be involved in TQ-induced apoptosis in MG63 by showing the cleavage of caspases-9 and -3. Oxidative stress and mitochondrial O(2)(*-) generation in isolated rat mitochondria were enhanced by TQ as measured by the dose-dependent reduction in aconitase enzyme activity and Amplex Red oxidation respectively. TQ-induced oxidative damage, reflected by an increase in gamma-H2AX foci and increased protein expression levels of gamma-H2AX and the DNA repair enzyme, NBS1, was more pronounced in MNNG/HOS than in MG63. We suggest that the resistance of MNNG/HOS cells to drug-induced apoptosis is caused by the up-regulation of p21(WAF1) by the mutant p53 (transcriptional activity was shown by p53 siRNA treatment) which induces cell cycle arrest and allows to repair DNA damage. Collectively, these findings show that TQ induces p53-independent apoptosis in human osteosarcoma cells. As the loss of p53 function is frequently observed in osteosarcoma patients, our data suggest the potential clinical usefulness of TQ for the treatment of these malignancies.
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PMID:Lack of p53 augments thymoquinone-induced apoptosis and caspase activation in human osteosarcoma cells. 1721 78

Pro-carcinogens, such as benzo[a]pyrene (B[a]P), that are exogenous ligands of the aromatic hydrocarbon receptor may influence the susceptibility of target-cell populations through the up-regulation of cytochrome P450 (CYP) mixed function oxidases. We examined whether the growth kinetics of MCF-7 cells might determine the level of up-regulation of CYP1A1, CYP1A2 or CYP1B1 by B[a]P, and whether this could then influence subsequent levels of DNA damage. Cell cultures manipulated to be G(0)/G(1)-phase concentrated, S-phase concentrated or G(2)/M-phase concentrated were treated with B[a]P and the expression levels of CYP1A1, CYP1A2, CYP1B1, cyclin-dependent kinase inhibitor 1A [CDKN1A (P21(WAF1/CIP1))], B-cell leukaemia/lymphoma-2 (BCL-2), and Bcl-2-associated X levels were determined. Levels of DNA damage were measured as DNA single-strand breaks (SSBs) by the alkaline single-cell gel electrophoresis (comet) assay or as DNA adducts by (32)P-postlabelling analysis. B[a]P-induced up-regulation of CYP1A1 was >100-fold in S-phase-concentrated cells, but in G(0)/G(1)-phase- or G(2)/M-phase-concentrated cultures up-regulation occurred to a significantly lower extent. Consistent with this, B[a]P-treated S-phase-concentrated cultures exhibited markedly up-regulated P21(WAF1/CIP1), higher levels of dose-related increases in DNA SSBs, and increased DNA adduct levels presumably as a result of CYP1A1-mediated activation of B[a]P to B[a]P-diol-epoxide compared with the cultures enriched for the other cell cycle phases. Growth kinetics in vitro may be an important predeterminant of susceptibility to an exogenous pro-carcinogen in short-term test systems and these findings have important implications when extrapolating such results to a particular target-cell population in vivo.
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PMID:Growth kinetics in MCF-7 cells modulate benzo[a]pyrene-induced CYP1A1 up-regulation. 1723 83

Recently, we reported that GM-CSF showed therapeutic effects on the spinal cord injury (SCI) in rat model possibly via its anti-apoptotic activity in the nervous system. This study investigated the molecular mechanism of its anti-apoptotic and neuroprotective effects in N2a neuroblastoma cells and in rat SCI model. GM-CSF inhibited staurosporine-induced cytotoxicity and apoptosis of N2a cells. Single administration of GM-CSF either intraperitoneally or locally using a gelfoam, clearly reduced the apoptotic events in the surrounding region of the injury site in rat SCI model. Immunohistochemical analysis showed that apoptosis of cells occurred mainly in the neurons, but not significantly in the astrocytes in the surrounding regions. In both N2a cells and in rat SCI model, GM-CSF actually reduced the expression of pro-apoptotic proteins (p53, p21(WAF1/CIP1) and Bax), while further induced that of an anti-apoptotic protein (Bcl-2). In the Basso-Beattie-Bresnahan (BBB) locomotor test, the single GM-CSF administration showed better behavioral recovery than the untreated control only at early times within 1 week after injury. Overall, GM-CSF was shown to exert its neuroprotective effect on the neural injury by regulating the expression of apoptosis related genes, providing the molecular basis on its anti-apoptotic activity. Longer administration of GM-CSF appeared to be necessary for the sustained functional recovery from SCI.
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PMID:GM-CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis-related proteins. 1733 4

IFN regulatory factor (IRF)-1 and IRF-2 are generally regarded as a tumor suppressor and an oncoprotein, respectively. However, little is known about their expression and function in esophageal squamous cell carcinomas (ESCC). In our present work, IRF-1 expression was decreased and IRF-2 expression was increased in ESCCs compared with matched normal esophageal tissues. Moreover, statistical data indicated that IRF-2 expression was tightly correlated with progression of ESCCs. As expected, overexpression of either IRF-1 or IRF-2 in an ESCC cell line resulted in either suppression or enhancement of cell growth, respectively. Also, proliferation- and apoptosis-related molecules (p21(WAF1/CIP1), cyclin-D1, Bcl-2, and histone H4) were regulated by IRF-1 and IRF-2. Additionally, high levels of IRF-2 blocked the function of IRF-1 by preventing the latter from translocating into the nucleus; in contrast, knock down of IRF-2 by small interfering RNA permitted nuclear localization and activity of IRF-1. In vivo assay using nude mice indicated that the tumorigenicity of ESCC cells was enhanced with IRF-2 overexpression but dramatically attenuated after forced expression of IRF-1. In conclusion, IRF-1 and IRF-2 are able to regulate tumorigenicity of ESCC cells as antioncoprotein and oncoprotein, respectively. Relative amounts of IRF-1 to IRF-2 are functionally very important for the development and progression of ESCCs, and reduction of the ratio of IRF-1/IRF-2 may lead to the enhancement of tumorigenicity of ESCC cells. Therefore, levels of IRF-1 and IRF-2 are useful indicators in diagnosis and prognosis for ESCCs, and these molecules are potential drug targets for ESCC therapy.
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PMID:Involvement of IFN regulatory factor (IRF)-1 and IRF-2 in the formation and progression of human esophageal cancers. 1736 71

Tumor growth depends on 2 distinctive pathways: cell proliferation and apoptosis. The p53 pathway is an important regulator of the cell cycle as it triggers growth arrest or leads to apoptosis in response to cellular stress and therefore is commonly targeted during tumorigenesis. Apoptosis is also controlled by the Bcl-2 family, which includes proapoptotic and antiapoptotic proteins. The aim of this study was to investigate the expression of proteins that are involved in the p53 pathway and apoptosis in different types of soft tissue sarcomas and to correlate the expression of these proteins with the histologic grade of sarcoma cases. One hundred fifty-two cases of different types of soft tissue sarcomas were analyzed. The cases consisted of 54 low-grade, 40 intermediate-grade, and 58 high-grade sarcomas. Immunohistochemical stains for p21(WAF1/CIP1), p53, Mdm2, Bcl-2, and Bax proteins were carried out on tissue microarrays. Nuclear reactivity for p53 was detected in 49 cases (32.2%). Overexpression of Mdm2 was found in 18 cases (11.8%) and p21(WAF1/CIP1) immunostaining was seen in 28 tumors (18.4%). p53 and p21(WAF1/CIP1) expression correlated with the tumor grade (low grade, 5.6% and 3.7%; intermediate grade, 22.5% and 20%; high grade, 63.8% and 31%, respectively). Expression of Bax protein was a common finding in soft tissue sarcoma cases. It was detected in 141 cases (92.8%). Bcl-2 was identified in 59 tumors (38.8%) and was more prevalent in high-grade sarcomas (low grade, 25.9%; intermediate grade, 32.5%; high grade, 55.2%). It was concluded that alterations in the p53 pathway and genes that regulate apoptosis are common events in soft tissue sarcomas. The expression of p53, p21(WAF1/CIP1), and Bcl-2 is closely associated with the histologic grade of the tumor, and therefore these proteins may be used as prognostic markers.
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PMID:Immunoreactivity of p53, Mdm2, p21(WAF1/CIP1) Bcl-2, and Bax in soft tissue sarcomas: correlation with histologic grade. 1753 10

Resveratrol, a polyphenol found in numerous plant species, including mulberries, peanuts and grapes, has shown to possess chemopreventive properties against several cancers, and cardiovascular diseases. Recently, resveratrol has been shown to have positive effects on age longevity, lipid levels and a preventative quality against certain cancers and viral infections. Resveratrol induces apoptosis by up-regulating the expression of Bax, Bak, PUMA, Noxa, Bim, p53, TRAIL, TRAIL-R1/DR4 and TRAIL-R2/DR5 and simultaneously down-regulating the expression of Bcl-2, Bcl-XL, Mcl-1 and survivin. Resveratrol causes growth arrest at G1 and G1/S phases of cell cycle by inducing the expression of CDK inhibitors p21/WAF1/CIP1 and p27/KIP1. Resveratrol has also been shown to reduce inflammation via inhibition of prostaglandin production, cyclooxygenase-2 activity, and nuclear factor-kappaB activity. Modulation of cell signaling pathway by resveratrol explains its diverse bioactivities related with human health. Resveratrol also potentiates the apoptotic effects of cytokines, chemotherapeutic agents and gamma-radiation. Pharmacokinetic and pharmacodynamic studies demonstrated that the main target organs of resveratrol are liver and kidney, and it is metabolized by hydroxylation, glucuronidation, sulfation and hydrogenation. As a chemoprevention agent, resveratrol has been shown to inhibit tumor initiation, promotion, and progression. There is growing evidence that resveratrol can prevent or delay the onset of various cancers, heart diseases, ischemic and chemically induced injuries, pathological inflammation and viral infections. This review summarizes the molecular mechanisms of resveratrol and its clinical benefits for human diseases.
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PMID:Chemoprevention by resveratrol: molecular mechanisms and therapeutic potential. 1756 14

Epidemiological data suggest that epigallocatechin-3-gallate (EGCG) possesses chemopreventive properties against cancer. In this study, we examined the molecular mechanisms of EGCG in human pancreatic cancer cells. EGCG caused growth arrest at G1 stage of cell cycle through regulation of cyclin D1, cdk4, cdk6, p21/WAF1/CIP1 and p27/KIP1, and induced apoptosis through generation of reactive oxygen species and activation of caspase-3 and caspase-9. EGCG inhibited expressions of Bcl-2 and Bcl-XL and induced expressions of Bax, Bak, Bcl-XS and PUMA. Mouse embryonic fibroblasts (MEFs) derived from Bax and Bak double knockout mice exhibited greater protection against EGCG-induced apoptosis than wild-type or single knockout MEFs. EGCG caused Bax activation in p53 -/- MEFs, suggesting that EGCG can induce apoptosis in the absence of p53. Furthermore, the activities of Ras, Raf-1 and ERK1/2 were inhibited, whereas the activities of MEKK1, JNK1/2 and p38 MAP kinases were induced by EGCG. Inhibition of cRaf-1 or ERK enhanced EGCG-induced apoptosis, whereas inhibition of JNK or p38 MAP kinase inhibited EGCG-induced apoptosis. EGCG inhibited the activation of p90 ribosomal protein S6 kinase, and induced the activation of cJUN. Our results suggest that EGCG induces growth arrest and apoptosis through multiple mechanisms, and can be used for pancreatic cancer prevention.
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PMID:Epigallocatechin-3-gallate inhibits cell cycle and induces apoptosis in pancreatic cancer. 1756 28


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