UNIPROT:P10415 - FACTA Search

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pancreatic cancer remains the fourth most common cause of cancer-related death in the United States. Notch signaling plays a critical role in maintaining the balance among cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. To characterize Notch pathway function in pancreatic cancer cells, we explored the consequences of down-regulation of Notch-1 in BxPC-3, HPAC, and PANC-1 pancreatic cancer cells. Using multiple cellular and molecular approaches such as 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, apoptosis assay, flow cytometry, gene transfection, real-time reverse transcription-PCR (RT-PCR), Western blotting, and electrophoretic mobility shift assay for measuring DNA binding activity of nuclear factor kappaB (NF-kappaB), we found that down-regulation of Notch-1 inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1 down-regulation also increased cell population in the G(0)-G(1) phase. Compared with control, small interfering RNA-transfected cells decreased expression of cyclin A, cyclin D1, and cyclin-dependent kinase 2. We found up-regulation of p21 and p27, which was correlated with the cell cycle changes. In addition, Notch-1 down-regulation also induced apoptosis, which could be due to decreased Bcl-2 and Bcl-X(L) protein expression in pancreatic cancer cells. Because Notch-1 is known to cross-talk with another major cell growth and apoptotic regulatory pathway (i.e., NF-kappaB), we found that NF-kappaB is a downstream target of Notch because down-regulation of Notch reduced NF-kappaB activity. We also found that genistein, a prominent isoflavone, could be an active agent for the down-regulation of the Notch pathway. These findings suggest that Notch-1 down-regulation, especially by genistein, could be a novel therapeutic approach for the treatment of pancreatic cancer.
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PMID:Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. 3027 73

Chemotherapy has produced unsatisfactory results in pancreas cancer and novel approaches, including treatment tailoring by pharmacogenetic analysis and new molecular-targeted drugs, are required. The scarcity of effective therapies may reflect the lack of knowledge about the influence of tumor-related molecular abnormalities on responsiveness to drugs. Advances in the understanding of pancreas cancer biology have been made over the past decade, including the discovery of critical mutations in oncogenes (i.e., K-Ras) as well as the loss of tumor suppressor genes, such as TP53 and p16(INK4). Other studies showed the dysregulation of the expression of proteins involved in the control of cell cycle, proliferation, apoptosis, and invasiveness, such as Bcl-2, Akt, mdm2, and epidermal growth factor receptor. These characteristics might contribute to the aggressive behavior of pancreatic cancer and influence response to treatment. Indeed, the inactivation of p53 may explain the relative resistance to 5-fluorouracil, whereas Bcl-2 overexpression is associated with reduced sensitivity to gemcitabine. However, the future challenge of pancreas cancer chemotherapy relies on the identification of molecular markers that help in the selection of drugs best suited to the individual patient. Recent pharmacogenetic studies focused on genes encoding proteins directly involved in drug activity, showing the role of thymidylate synthase and human equilibrative nucleoside transporter-1 as prognostic factor in 5-fluorouracil- and gemcitabine-treated patients, respectively. Finally, inhibitors of signal transduction and angiogenesis are under extensive investigation, and several prospective trials have been devoted to this area. Pharmacogenetics is likely to play a central role in the personalization of treatment, to stratify patients based on their likelihood of response to both standard agents (i.e., gemcitabine/nucleoside transporters) and targeted treatments (i.e., epidermal growth factor receptor gene mutations and/or amplification and tyrosine kinase inhibitors), Thus, molecular analysis should be implemented in the optimal management of the patient affected by pancreatic adenocarcinoma.
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PMID:Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer. 1681 96

Pancreatic cancer is associated with low responsiveness to conventional chemotherapies and its incidence nearly equals its death rate. This warrants the development of novel mechanism-based approaches for the management of pancreatic cancer. This study was designed to determine the potential of sanguinarine, a plant alkaloid known to possess strong antimicrobial, anti-inflammatory, and antioxidant activities, against human pancreatic carcinoma cells. Employing human pancreatic carcinoma AsPC-1 and BxPC-3 cells, we specifically evaluated the pro-apoptotic and cell cycle deregulatory effects of sanguinarine and evaluated the involvement of Bcl-2 family proteins and p53 as the mechanism of the biological effects of sanguinarine. Our data demonstrated that sanguinarine (at low concentrations of 0.1-10 microM; for 24 h) treatment to AsPC-1 and BxPC-3 cells resulted in a dose dependent (i) inhibition of viability and growth, (ii) colony formation ability, (iii) induction of apoptosis, and (iv) G0-G1 phase cell cycle arrest. Further, sanguinarine-treatment to AsPC-1 and BxPC-3 cells resulted in a dose dependent (i) increase in pro-apoptotic Bax, Bid and Bak proteins; (ii) decrease in anti-apoptotic Bcl-2 and Bcl-X(L) proteins; and (iii) decrease in p53 with an increase in its phosphorylation. Based on our study, we suggest that sanguinarine may be developed as an agent for the management of pancreatic cancer. Indeed, more in depth studies both in vitro as well as in vivo in appropriate relevant animal models are needed to strengthen this suggestion.
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PMID:Sanguinarine induces apoptosis of human pancreatic carcinoma AsPC-1 and BxPC-3 cells via modulations in Bcl-2 family proteins. 1700 19

Pancreatic cancer (PC) is characterized as one of the deadliest malignancies and its treatment is a great challenge to clinical oncologists. Expression of COX-2 is detectable in 75% of PCs among which 50% showed overexpression, suggesting the importance of COX-2 enzyme and its metabolic product prostaglandin E2 (PGE(2)) in PC. Here the authors report the synthesis and biological activity of a novel COX-2 inhibitor, FPA-306, and its effects on PC cells with different levels of COX-2 expression. Using MTT assay, the authors found a significant growth inhibition of BxPC-3 cells treated by FPA-306 with an IC(50) of 10 micromol/L, which was lower than that of ketoprofen (IC(50) = 35.4 micromol/L) and celecoxib (IC(50) > 100 micromol/L). There was no such effect found in MIAPaCa cell line, which does not express COX-2. The authors also found dose dependent reduction in cell survival and induction of apoptosis by FPA-306 treatment in BxPC-3 cells but not in MIAPaCa cells. These results were correlated with apoptosis data and secreted PGE(2) levels. The molecular modeling of FPA-306 in the COX-2 active site showed that FPA-306 is potentially able to inhibit the activity of enzyme by blocking the active site, thereby resulting in decreased PGE(2) production. The authors also found a significant reduction of COX-2 at the mRNA and protein levels together with downregulation of NF-kappaB DNA binding activity and its downstream genes, Bcl-2 and survivin. These results suggest that FPA-306 is an effective and potent agent in inhibiting the growth of PC cells.
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PMID:A novel copper complex of 3-benzoyl-alpha methyl benzene acetic acid with antitumor activity mediated via cyclooxygenase pathway. 1713 40

We have previously shown that the leukotriene B4 receptor antagonist, LY293111 inhibits proliferation and induces apoptosis in human pancreatic cancer cells both in vitro and in vivo. In the current study, we investigated the molecular mechanisms of LY293111-induced apoptosis and cell cycle arrest. Two human pancreatic cancer cell lines were used in this study, MiaPaCa-2 and AsPC-1. Cell cycle analysis by flow cytometry showed a dramatic increase in the percentage of apoptotic cells as well as S-phase arrest after treatment with 250 nmol/l LY293111 for up to 48 h. Western blotting indicated that LY293111 treatment induced cytochrome c release from the mitochondria into the cytosol, accompanied by caspase-9, caspase-7 and caspase-3 activation, and cleavage of poly ADP-ribose polymerase. Caspase-8 was not activated by LY293111. A decrease was found in the expression of the antiapoptotic proteins, Bcl-2 and Mcl-1, and an increase in the proapoptotic protein, Bax. LY293111 reduced the expression of CDK2, cyclin A and cyclin E, consistent with the S-phase arrest observed in these cells. The expression of cyclin-dependent kinase inhibitors, p21 and p27 was not affected by LY293111 treatment. In conclusion, LY293111 induces apoptosis in human pancreatic cancer cells through the mitochondria-mediated pathway. LY293111 also induces S-phase arrest with downregulation of CDK2, cyclin A and cyclin E. Blockade of leukotriene B4 metabolic pathway may provide a novel treatment for human pancreatic cancer.
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PMID:Leukotriene B4 receptor antagonist LY293111 induces S-phase cell cycle arrest and apoptosis in human pancreatic cancer cells. 1741 22

Pancreatic adenocarcinoma is characterized by a poor prognosis and lack of response to conventional therapy. The purpose of this study was to investigate the effects of triptolide (TL) on proliferation and apoptosis of pancreatic cancer cells in vitro. We found that TL induced prominent growth inhibition and apoptosis in human pancreatic cell lines. In addition, TL treatment significantly down-regulated 5-lipoxygenase (5-LOX) expression, as well as downstream leukotriene B4 (LTB4) production, in these cell lines. Furthermore, overexpression of 5-LOX in SW1990 cell lines or exogenous LTB4 made them more resistant to TL-induced apoptosis, which was correlated with increased Bcl-2 expression. Taken together, these findings suggest that inhibition of the 5-LOX pathway of arachidonic acid metabolism is associated with the anti-proliferation activity of TL. We also provide evidence that TL has clinical therapeutic value for patients with pancreatic cancer.
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PMID:Suppression of 5-lipoxygenase gene is involved in triptolide-induced apoptosis in pancreatic tumor cell lines. 1743 78

Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-kappaB (NF-kappaB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-kappaB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-kappaB activation, and expression of NF-kappaB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31(+) microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing proliferation, angiogenesis, NF-kappaB, and NF-kappaB-regulated gene products.
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PMID:Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. 1744 Jan

FTY720, a synthetic compound produced by modification of a metabolite from Isaria sinclairii, is known as a unique immunosuppressive agent that exerts its activity by inducing apoptosis of lymphocytes [S. Suzuki, FTY720: Mechanisms of action and its effect on organ transplantation, Transplant. Proc. 31 (1999) 2779-2782]. Additionally, it has been found that FTY720 has inhibitory effects on various cancer growth and metastasis [J.D. Wang, S. Takahara, N. Nonomura, Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation, Prostate 40 (1999) 50-55]. To investigate its effect on the growth and metastasis of pancreatic cancer, FTY720 was used to treat three pancreatic cancer cell lines (BxPC-3, AsPC-1, and PANC-1). The MTT assay and flow cytometry were used to evaluate the cell death after FTY720 treatment; the wound closure assay, three-dimensional (3D) Matrigel assay, and invasive assay were used to evaluate the migration, colony formation and invasion abilities after FTY720 treatment, respectively. Protein expression in BxPC-3, AsPC-1, and PANC-1 cells after FTY720 treatment was detected by Western blotting. The MTT assay indicated that the growth of pancreatic cancer cells could be inhibited by FTY720 at various concentrations between 0 and 17 microM in a dose-dependent manner, which was also confirmed by flow cytometry. The wound closure assay, 3D Matrigel assay and cell invasion assay all showed that FTY720 significantly suppressed migration, colony formation and invasion ability of cancer cells at concentrations from 5 to 17 microM. After FTY720 treatment, the phospho-Akt, Bcl-2, pro-caspase-3 expression were down-regulated while the caspase-9 protein expression was increased. In conclusion, FTY720 can inhibit the growth, migration and invasion of pancreatic cancer cells. Our study provides a preclinical support for chemotherapeutic approach with FTY720 for the treatment of pancreatic cancer.
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PMID:FTY720, a synthetic compound from Isaria sinclairii, inhibits proliferation and induces apoptosis in pancreatic cancer cells. 1746 18

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

The gene encoding lysyl oxidase (LOX) was identified as the ras recision gene (rrg), with the ability to revert Ras-mediated transformation of NIH 3T3 fibroblasts. Mutations in RAS genes have been found in approximately 25% of lung cancers and in 85% of pancreatic cancers. In microarray analysis, these cancers were found to display reduced LOX gene expression. Thus, the ability of the LOX gene to repress the transformed phenotype of these cancer cells was tested. LOX is synthesized as a 50-kDa secreted precursor Pro-LOX that is processed to the 32-kDa active enzyme (LOX) and to an 18-kDa propeptide (LOX-PP). Recently, we mapped the rrg activity of Pro-LOX to the LOX-PP in Ras-transformed NIH 3T3 cells. Ectopic Pro-LOX and LOX-PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal-regulated kinase (ERK) and Akt, with LOX-PP showing substantially higher activity. Similarly, LOX-PP expression in PANC-1 pancreatic cancer cells effectively reduced ERK and Akt activity and inhibited growth in soft agar and ability of these cells to migrate. Nuclear Factor-kappaB (NF-kappaB) and its target gene BCL2, which are overexpressed in 70% to 75% of pancreatic cancers, have recently been implicated in invasive phenotype. LOX-PP substantially reduced NF-kappaB and Bcl-2 levels. Reintroduction of Bcl-2 into PANC-1 or H1299 cells expressing LOX-PP restored the transformed phenotype, suggesting that Bcl-2 is an essential target. Thus, LOX-PP potently inhibits invasive phenotype of lung and pancreatic cancer cells, suggesting potential therapeutic applications in treatment of these cancers.
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PMID:Repression of BCL2 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells. 1761 86

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