Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trefoil factor (TFF)1 is synthesized and secreted by the normal stomach mucosa and by the gastrointestinal cells of injured tissues. The link between mouse TFF1 inactivation and the fully penetrant antropyloric tumor phenotype prompted the classification of TFF1 as a gastric tumor suppressor gene. Accordingly, altered expression, deletion, and/or mutations of the TFF1 gene are frequently observed in human gastric carcinomas. The present study was undertaken to address the nature of the cellular and molecular mechanisms targeted by TFF1 signalling. TFF1 effects were investigated in IEC18, HCT116, and AGS gastrointestinal cells treated with recombinant human TFF1, and in stably transfected HCT116 cells synthesizing constitutive or doxycycline-induced human TFF1. We observed that TFF1 triggers two types of cellular responses. On one hand, TFF1 lowers cell proliferation by delaying G1-S cell phase transition. This results from a TFF1-mediated increase in the levels of cyclin-dependent kinase inhibitors of both the INK4 and CIP subfamilies, leading to lower E2F transcriptional activity. On the other hand, TFF1 protects cells from chemical-, anchorage-free-, or Bad-induced apoptosis. In this process, TFF1 signalling targets the active form of caspase-9. Together, these results provide the first evidence of a dual antiproliferative and antiapoptotic role for TFF1. Similar paradoxical functions have been reported for tumor suppressor genes involved in cell differentiation, a function consistent with TFF1.
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PMID:The trefoil factor 1 participates in gastrointestinal cell differentiation by delaying G1-S phase transition and reducing apoptosis. 1203 70

Aspirin-induced apoptosis is one of the important mechanisms for its antitumour effect against gastric cancer. We aimed at investigating the involvement of bcl-2 family members in the apoptotic pathway in gastric cancer. Gastric cancer cell line AGS and MKN-45 were observed as to cell growth inhibition and induction of apoptosis in response to treatment with aspirin. Cell proliferation was measured by MTT assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole staining. Protein expression was determined by western blotting. We showed that aspirin activated caspase-8, caspase-9 and capase-3, cleaved and translocated Bid, induced a conformational change in and translocation of Bax and cytochrome c release. In addition, suppression of caspase-8 with the specific inhibitor z-IETD-fmk, as well as the pan-caspase inhibitor z-VAD-fmk, prevented Bid cleavage and subsequent apoptosis. The caspase inhibitors failed to abolish the effects on Bax activation. In conclusion, our results identify a role of caspase-8/Bid and activation of Bax as a novel mechanism for aspirin-induced apoptosis in gastric cancer.
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PMID:Activation of the caspase-8/Bid and Bax pathways in aspirin-induced apoptosis in gastric cancer. 1557 84

This study was undertaken to determine whether the Bcl-2 family proteins and Smac are regulators of aspirin-mediated apoptosis in a gastric mucosal cell line known as AGS cells. Cells were incubated with varying concentrations of acetylsalicylic acid (ASA; 2-40 mM), with or without preincubation of caspase inhibitors. Apoptosis was characterized by Hoechst staining and DNA-histone-associated complex formation. Antiapoptotic Bcl-2, proapoptotic Bax and Bid, Smac, and cytochrome-c oxidase (COX IV) were analyzed by Western blot analyses from cytosol and mitochondrial fractions. ASA downregulated Bcl-2 protein expression and induced Bax translocation into the mitochondria and cleavage of Bid. In contrast, expression of Smac was significantly decreased in mitochondrial fractions of ASA-treated cells. Bax and Bid involvement in apoptosis regulation was dependent on caspase activation, because caspase-8 inhibition suppressed Bax translocation and Bid processing. Caspase-9 inhibition prevented Smac release from mitochondria. Additionally, increased expression of the oxidative phosphorylation enzyme COX IV was observed in mitochondrial fractions exposed to ASA at concentrations >5 mM. Although caspase-8 inhibition had no effect on aspirin-induced apoptosis and DNA-histone complex formation, caspase-9 inhibition significantly decreased both of these events. We conclude that Bcl-2 protein family members and Smac regulate the apoptotic pathway in a caspase-dependent manner. Our results indicate also that mitochondrial integration and oxidative phosphorylation play a critical role in the pathogenesis of apoptosis in human gastric epithelial cells.
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PMID:Role of mitochondria in aspirin-induced apoptosis in human gastric epithelial cells. 1597 87

t-Darpp is a cancer-related truncated isoform of Darpp-32 (dopamine and cyclic-AMP-regulated phosphoprotein of M(r) 32,000). We detected overexpression of t-Darpp mRNA in two thirds of gastric cancers compared with normal samples (P = 0.004). Using 20 micromol/L ceramide treatment as a model for induction of apoptosis in AGS cancer cells, we found that expression of t-Darpp led to an increase in Bcl2 protein levels and blocked the activation of caspase-3 and caspase-9. The MitoCapture mitochondrial apoptosis and cytochrome c release assays indicated that t-Darpp expression enforces the mitochondrial transmembrane potential and protects against ceramide-induced apoptosis. Interestingly, the expression of t-Darpp in AGS cells led to >or=2-fold increase in Akt kinase activity with an increase in protein levels of p-Ser(473) Akt and p-Ser(9) GSK3 beta. These findings were further confirmed using tetracycline-inducible AGS cells stably expressing t-Darpp. We also showed transcriptional up-regulation of Bcl2 using the luciferase assay with Bcl2 reporter containing P1 full promoter, quantitative reverse transcription-PCR, and t-Darpp small interfering RNA. The Bcl2 promoter contains binding sites for cyclic AMP-responsive element binding protein CREB/ATF1 transcription factors and using the electrophoretic mobility shift assay with a CREB response element, we detected a stronger binding in t-Darpp-expressing cells. The t-Darpp expression led to an increase in expression and phosphorylation of CREB and ATF-1 transcription factors that were required for up-regulating Bcl2 levels. Indeed, knockdown of Akt, CREB, or ATF1 in t-Darpp-expressing cells reduced Bcl2 protein levels. In conclusion, the t-Darpp/Akt axis underscores a novel oncogenic potential of t-Darpp in gastric carcinogenesis and resistance to drug-induced apoptosis.
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PMID:t-Darpp promotes cancer cell survival by up-regulation of Bcl2 through Akt-dependent mechanism. 1819 33

Rhus verniciflua Stokes (RVS) has been used in traditional Eastern Asia medicine for the treatment of gastritis and stomach cancer, although the mechanism for its biological activity remains to be elucidated. We previously established that an ethanol extract of RVS-induced G(1)-cell cycle arrest via accumulation of p27(Kip1) controlled by Skp2 reduction and apoptosis in AGS human gastric cancer cells. Here, we showed that an ethanol extract of RVS-induced apoptosis via caspase-9 activation (mitochondrial death pathway) is mediated by the loss of mitochondrial membrane potential (MMP, Deltapsi(m)) and the release of cytochrome C from the mitochondrial intermembrane space. In addition, an ethanol extract of RVS inactivated PI3K-Akt/PKB kinase in a time-dependent manner. Moreover, combined treatment of an ethanol extract of RVS and LY294002 (a PI3K inhibitor) markedly increased apoptosis compared to treatment with an ethanol extract of RVS alone. The role of PI3K-Akt/PKB in this process was confirmed by constitutive expression of inactive mutants of this kinase in AGS cells. Finally, siRNA-mediated knockdown of Akt/PKB expression resulted in a significant reduction in AGS cell proliferation. Taken together, these results suggest that an ethanol extract of RVS induces apoptosis via a mitochondrial death pathway in human gastric cancer cells, but not in normal cells, and inhibition of the PI3K-Akt/PKB pathway enhanced the mitochondrial death pathway.
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PMID:Inhibition of the PI3K-Akt/PKB survival pathway enhanced an ethanol extract of Rhus verniciflua Stokes-induced apoptosis via a mitochondrial pathway in AGS gastric cancer cell lines. 1837 93

The seed of Strychnos nux-vomica (Loganiaceae) has been used in traditional Oriental medicine as a folk remedy for the treatment of cancer. However, the mechanism responsible for the anticancer effects of Strychni Semen is not clearly understood. The study tested whether and how the water extract of Strychni Semen (ESS) treatment would affect the growth of AGS human gastric carcinoma cells. ESS was found to inhibit the growth of AGS cells in a concentration-dependent manner. Cell cycle analysis showed G2/M phase arrest and apoptosis in AGS cells following ESS treatment. ESS-mediated G2/M arrest was found to be associated with up-regulation of cyclin A, Cdc2, tumor suppressor p53 and cyclin dependent kinase (Cdk) inhibitor p21(WAF1/CIP1), whereas the expressions of other G2/M regulatory proteins, including cyclin B1 and Cdk2, were down-regulated compared with the control. The induction of apoptotic cell death by ESS was associated with down-regulation of anti-apoptotic Bcl-2 and up-regulation of pro-apoptotic Bax expression. Further results indicate that caspase-3, caspase-8 and caspase-9 are all activated by ESS, together with cleavage of downstream caspase-3 target proteins. Taken together, the results of this study suggest the involvement of multiple signaling pathways targeted by ESS in mediating G2/M cell cycle arrest and apoptosis in AGS cells, and warrant further investigation.
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PMID:Induction of G2/M arrest and apoptosis by water extract of Strychni Semen in human gastric carcinoma AGS cells. 1844 45

Interferon regulatory factor-1 (IRF-1) is a transcription factor that acts as a tumor suppressor and causes apoptosis in cancer cells. We evaluated IRF-1-induced apoptosis in gastric cancer cell lines. We established stable clones in AGS cells that have a tetracycline-inducible IRF-1 expression system. We used these clones and recombinant adenovirus expressing IRF-1 to explore the mechanism of IRF-1-induced apoptosis in gastric cancer. Expression of IRF-1 causes apoptosis in gastric cancer cell lines as shown by phosphatidylserine exposure and cleavage of caspase-8, caspase-3, and Bid with the mitochondrial release of cytochrome c. However, inhibition of caspase-8 and Bid did not inhibit apoptosis and did not decrease cleaved caspase-9 or mitochondrial release of cytochrome c. We then show that IRF-1 upregulates PUMA (p53 upregulated modulator of apoptosis), which is known to activate apoptosis by the intrinsic pathway; this can be p53-independent. IRF-1 binds to distinct sites in the promoter of PUMA and activates PUMA transcription. Moreover, molecular markers of mitochondrial apoptosis are eliminated in PUMA knockout and knockdown cells and phosphatidylserine exposure is decreased dramatically. Finally, we show that IFN-gamma induces IRF-1-mediated upregulation of PUMA in cancer cells. We conclude that IRF-1 can induce apoptosis by the intrinsic pathway independent of the extrinsic pathway by upregulation of PUMA.
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PMID:IRF-1 transcriptionally upregulates PUMA, which mediates the mitochondrial apoptotic pathway in IRF-1-induced apoptosis in cancer cells. 1985 30

The scaffold of 3,5-diaryl-1H-pyrazole was selected as a molecular template to synthesize novel growth-inhibitory agents in the present study. Our findings suggested that analogs bearing electron-withdrawing groups on one ring while electron-donating groups on another reveal significant activities. In particular, 26 bearing a 1,1'-biphenyl moiety displayed the most potent activity against OVCA, SW620, H460 and AGS cells with GI(50) values of 0.67, 0.89, 0.73 and 0.79 microM, respectively. The mechanistic study revealed that 26-mediated apoptosis-inducing effect on OVCA cells was, in part, attributed to the inhibition of protein kinase B/Akt activity, accompanied by the mitochondrial apoptotic pathway through the activation of caspase-9, caspase-3, as well as the cleavage of protein poly(ADP-ribose) polymerase (PARP) and DNA fragmentation. Further structure-activity relationship study employed by Comparative Molecular Field Analysis (CoMFA) was carried out with q(2) and R(2) values of 0.671 and 0.846, respectively.
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PMID:3,5-Diaryl-1H-pyrazole as a molecular scaffold for the synthesis of apoptosis-inducing agents. 2038 60

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as sulindac and indomethacin are a major cause of gastric erosions and ulcers. Induction of apoptosis by NSAIDs is an important mechanism involved. Understanding how NSAIDs affect genes that regulate apoptosis is useful for designing therapeutic or preventive strategies and for evaluating the efficacy of safer drugs being developed. We investigated whether growth arrest and DNA damage-inducible 45alpha (GADD45alpha), a stress signal response gene involved in regulation of DNA repair and induction of apoptosis, plays a part in NSAID-induced gastric mucosal injury and apoptosis in vivo in mice and in vitro in cultured human AGS and rat RGM-1 gastric epithelial cells. Intraperitoneal administration of sulindac and indomethacin both resulted in up-regulation of GADD45alpha expression and induction of significant injury and apoptosis in gastric mucosa of wild-type mice. GADD45alpha(-/-) mice were markedly more resistant to both sulindac- and indomethacin-induced gastric mucosal injury and apoptosis than wild-type mice. Sulindac sulfide and indomethacin treatments also concentration-dependently increased GADD45alpha expression and apoptosis in AGS and RGM-1 cells. Antisense suppression of GADD45alpha expression significantly reduced sulindac and indomethacin-induced activation of caspase-9 and apoptosis in AGS cells. Pretreatments with exogenous prostaglandins and small interfering RNA suppression of cyclooxygenase (COX)-1 and -2 did not affect up-regulation of GADD45alpha by sulindac sulfide and indomethacin in AGS cells. These findings indicate that GADD45alpha up-regulation is a COX-independent mechanism that is required for induction of severe gastric mucosal apoptosis and injury by NSAIDs, probably via a capase-9-dependent pathway of programmed cell death.
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PMID:Suppression of growth arrest and DNA damage-inducible 45alpha expression confers resistance to sulindac and indomethacin-induced gastric mucosal injury. 2049 52

We isolated a novel glycoprotein from the brown alga Laminaria japonica that has antiproliferative effects on HT-29 colon cancer cells. We also identified the mechanism by which this glycoprotein, named LJGP, induces apoptosis. MTS assays showed that LJGP inhibited the proliferation of several cancer cell lines (AGS, HepG2, HT-29) in a dose-dependent manner. Especially in HT-29 cells, proliferation was significantly decreased. LJGP treatment on HT-29 displayed several apoptotic features, such as DNA fragmentation, sub-G1 arrest, caspase-3 activation, and PARP degradation. Consistent with sub-G1 arrest, LJGP decreased the expression of Cdk2, cyclin E, cyclin D1, PCNA, E2F-1, and phosphorylated pRb. Furthermore, the increase of p27 expression was observed. We also determined that LJGP-induced apoptosis leads to the formation of a death-induced signaling complex of Fas, FADD, and procaspase-8. LJGP induced the reduction of mitochondrial membrane potential with activation of the Bcl-2 family of proteins and caspase-9. These findings suggest that LJGP inhibits HT-29 cell proliferation by inducing apoptosis, which may be mediated via multiple pathways, including the Fas signaling pathway, the mitochondrial pathway, and cell cycle arrest. Therefore, LJGP can be a useful treatment option for colon cancer in humans.
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PMID:A glycoprotein from Laminaria japonica induces apoptosis in HT-29 colon cancer cells. 2061 60


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