Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.22.62 (caspase-9)
7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4-Hydroxynonenal (HNE) is one of the most abundant aldehyde components of ox-LDL and it exerts various effects on intracellular and extracellular signaling cascades. In this mini-review, a brief synopsis of HNE-modulated signaling pathways will be presented mainly focused on cell death, including recent studies from our laboratory. The results of a number of studies demonstrate the ability of HNE to induce apoptosis and ROS formation in a dose-dependent manner. Several signaling pathways have been shown to be modulated by HNE, including MAP kinases, PKC isoforms, cell-cycle regulators, receptor tyrosine kinases and caspases. In order to get insight into the mechanisms of apoptotic response by HNE, MAP kinase and caspase activation pathways have been studied in 3T3 fibroblasts; HNE induced early activation of JNK and p38 proteins but down-regulated the basal activity of ERK-1/2. We have shown that HNE-induced release of cytochrome c from mitochondria, caspase-9 and caspase-3 activation. Activation of AP-1 along with increased c-Jun and phospho-c-Jun levels could be inhibited by pretreatment of cells with certain molecules such as resveratrol. Additionally, overexpression of dominant negative c-Jun and JNK1 in 3T3 fibroblasts prevented HNE-induced apoptosis, which indicated a role for JNK-c-Jun/AP-1 pathway. JNK-dependent induction of c-Jun/AP-1 activation data in the literature indicates a critical potential role for JNK in the cellular response against toxic products of lipid peroxidation.
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PMID:Apoptosis signalling by 4-hydroxynonenal: a role for JNK-c-Jun/AP-1 pathway. 1726 5

Continuous endoplasmic reticulum (ER) stress, such as the accumulation of unfolded proteins, results in cell death and relates to the pathogenesis of some neurodegenerative diseases. Treatment of brefeldin A, an inhibitor of transport between the ER and Golgi complex, induced cell death during 24 h, which accompanied activation of caspase-2, caspase-3 and caspase-9, starting at 12 h and increasing time-dependently up to 28 h. Caspase-2 was expressed and activated in not only mitochondria and cytosol, but also in the microsomal fraction containing ER and Golgi. Of note is that overexpression of Bcl-x(L) or Bcl-2 in PC12 cells markedly suppressed brefeldin A-induced activation of caspases and resulting cell death. Delivery of anti-Bcl-2 antibody into the Bcl-2-overexpressed cells again recovered apoptosis. While the brefeldin A-treatment induced the phosphorylation of both c-Jun N-terminal kinase (JNK) and p38 MAPK, overexpression of Bcl-x(L) or Bcl-2 reduced the prolonged phosphorylation of JNK, but not of p38 MAPK. Pretreatment with a JNK inhibitor, SP600125, suppressed the brefeldin A-induced caspase-2 activation and cell death significantly. Thus, our results suggest that protective effects of Bcl-x(L) and Bcl-2 against brefeldin A-induced cell death appear to be dependent on the regulation of JNK activation.
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PMID:Suppression of endoplasmic reticulum stress-induced caspase activation and cell death by the overexpression of Bcl-xL or Bcl-2. 1730 Oct 78

Ansamycin antibiotics that target heat shock protein 90 function are being developed as anticancer agents but are also known to be dose limiting in patients due to hepatotoxicity. Herein, to better understand how the normal tissue toxicity of geldanamycins could be ameliorated to improve the therapeutic index of these agents, we examined the interactions of 17-allylamino-17-demethoxygeldanamycin (17AAG) and the secondary bile acid deoxycholic acid (DCA) in hepatocytes and fibroblasts. DCA and 17AAG interacted in a greater than additive fashion to cause hepatocyte cell death within 2 to 6 h of coadministration. As single agents DCA, but not 17AAG, enhanced the activity of extracellular signal-regulated kinase 1/2, AKT, c-Jun NH(2)-terminal kinase 1/2 (JNK1/2), and p38 mitogen-activated protein kinase (MAPK). Combined exposure of cells to DCA and 17AAG further enhanced JNK1/2 and p38 MAPK activity. Inhibition of JNK1/2 or p38 MAPK, but not activator protein-1, suppressed the lethality of 17AAG and of 17AAG and DCA. Constitutive activation of AKT, but not MAPK/extracellular signal-regulated kinase kinase 1/2, suppressed 17AAG- and DCA-induced cell killing and reduced activation of JNK1/2. DCA and 17AAG exposure promoted association of BAX with mitochondria, and functional inhibition of BAX or caspase-9, but not of BID and caspase-8, suppressed 17AAG and DCA lethality. DCA and 17AAG interacted in a greater than additive fashion to promote and prolong the generation of reactive oxygen species (ROS). ROS-quenching agents, inhibition of mitochondrial function, expression of dominant-negative thioredoxin reductase, or expression of dominant-negative apoptosis signaling kinase 1 suppressed JNK1/2 and p38 MAPK activation and reduced cell killing after 17AAG and DCA exposure. The potentiation of DCA-induced ROS production by 17AAG was abolished by Ca(2+) chelation and ROS generation, and cell killing following 17AAG and DCA treatment was abolished in cells lacking expression of PKR-like endoplasmic reticulum kinase. Thus, DCA and 17AAG interact to stimulate Ca(2+)-dependent and PKR-like endoplasmic reticulum kinase-dependent ROS production; high levels of ROS promote intense activation of the p38 MAPK and JNK1/2 pathways that signal to activate the intrinsic apoptosis pathway.
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PMID:17-Allylamino-17-demethoxygeldanamycin enhances the lethality of deoxycholic acid in primary rodent hepatocytes and established cell lines. 1730 59

Studies on chemoprevention of cancer are generating increasing interest. The anti-neoplastic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) involves cyclooxygenase (COX)-dependent and COX-independent mechanisms. Evidence suggests that mitogen-activated protein kinases (MAPKs) may mediate apoptotic signaling induced by anti-neoplastic agents. While many reports have revealed the existence of MAPK activation in apoptosis induced by various stimuli, the signaling transduction pathways used by NSAIDs to trigger apoptosis in human renal cell carcinoma (RCC) remain largely unknown. Treatment of RCC 786-O cells with indomethacin resulted in growth regression and apoptosis. Caspase-dependent apoptosis was evidenced by the detection of enzymatic activities of caspase-3, caspase-6, and caspase-9 and suppression of toxicity using a caspase inhibitor. Indomethacin treatment was associated with increased expression of glucose-regulated protein 78 (GRP78) and C/EBP homologus protein (CHOP) and activation of ATF-6, characteristics of endoplasmic reticulum stress. In addition, the concomitant induction of peroxisome proliferator-activated receptor (PPAR), especially PPAR-beta, was apparent in treated cells. Western blotting revealed the activation of extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) with indomethacin treatment. Selective inhibitors of ERK, p38 MAPK, and JNK suppressed the induction of GRP78, CHOP, and PPAR-beta, attenuated indomethacin-induced cytotoxicity and reduced increased caspase activity. LY294002, a phosphoinositide-3 kinase (PI3K)/AKT inhibitor, and Trolox, an antioxidant, suppressed indomethacin-induced cytotoxicity and caspase activation. Furthermore, Trolox attenuated indomethacin-induced increased phosphorylation in ERK, p38 MAPK, JNK, and AKT. In conclusion, our findings establish a mechanistic link between the oxidative stress, PI3K/AKT pathway, MAPK pathway and indomethacin-induced cellular alterations and apoptosis in 786-O cells.
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PMID:Indomethacin induces apoptosis in 786-O renal cell carcinoma cells by activating mitogen-activated protein kinases and AKT. 1734 18

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, may have a potentiality as a structural template for rational drug design in killing cancer cells. Treatment of K562 cells with 0.3 microM of CTX III resulted in G2/M phase cell cycle arrest that was associated with a marked decline in protein levels of G2/M regulatory proteins including cyclin A, cyclin B1, Cdk2 and Cdc25C. In contrast to no effect on the phosphorylation of ERK, p38 MAPK and Akt, an activation of JNK was noted when K562 cells were exposed to CTX III. CTX III-mediated G2/M phase arrest and apoptosis were reduced by treatment with the JNK-specific inhibitor SP600125, but not by ERK and p38MAPK inhibitors. Further investigation showed that the specific JNK inhibitor, SP600125, reduced the activation of caspase-3, caspase-9, and reversed the decline in the expression of cyclin B1. Taken together, our data show for the first time that JNK, but not ERK, p38MAPK or Akt signaling, plays an important role in CTX III-mediated G2/M arrest and apoptosis in K562 cancer cells.
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PMID:Involvement of c-jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by cardiotoxin III (Naja naja atra) in K562 leukemia cells. 1736 2

Arsenic trioxide (As2O3) induces apoptosis in certain types of cancer cells. But the detailed mechanisms of As2O3 efficacy are not completely known. Here we demonstrate that As2O3 has a therapeutic effect on cervical cancer in vitro and in vivo. We investigated the As2O3-induced apoptosis in various cervical cancer cells. The apoptosis was triggered by mitochondrial pathway and associated with dissociation of Bcl-2 from Bax and VDAC, then the release of cytochrome c from Bax and VDAC channel, resulting in the activation of caspase-9 and caspase-3. The overexpression of Bcl-2 counteracted the As2O3-mediated apoptosis. The As2O3 treatment also resulted in an increased M phase cell cycle distribution by inducing microtubule polymerization. Two independent death-signaling pathways in cervical cancer cells were activated, one dominated by JNK/p38/GADD45 and one by p53 signals. Further investigation involving assessment of As2O3 on tumor cell growth in mice indicated that As203 also inhibited in vivo tumor growth. As2O3 as an inhibitor of cervical cancer proliferation both in vitro and in vivo suggests a potential clinical application in cervical cancer therapies.
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PMID:Therapeutic effect of arsenic trioxide (As2O3) on cervical cancer in vitro and in vivo through apoptosis induction. 1737 90

Death receptor-mediated tumor cell death, either alone or in combination with other anticancer drugs, is considered as a new strategy for anticancer therapy. In this study, we have investigated the effects and molecular mechanisms of 5-aminoimidazole-4-carboxamide riboside [AICAR; a pharmacologic activator of AMP-activated protein kinase (AMPK)] in sensitizing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- and TNFalpha-induced apoptosis of human colon cancer HCT116 cells. The cytotoxic action of AICAR requires AMPK activation and may occur at various stages of apoptotic pathways. AICAR cotreatment with either TRAIL or TNFalpha enhances activities of caspase-8, caspase-9, and caspase-3; down-regulates the antiapoptotic protein Bcl-2; increases the cleavage of Bid and results in the decrease of mitochondrial membrane potential; potentiates activation of p38 and c-Jun NH(2)-terminal kinase; and inhibits nuclear factor-kappaB activity. In addition, this sensitized cell apoptosis was neither observed in p53-null HCT116 cells nor affected by the cotreatment with mevalonate. In summary, we have developed a novel strategy of combining AICAR with TRAIL for the treatment of colon cancer cells. The sensitization effect of AICAR in cell apoptosis was mediated through AMPK pathway, requires p53 activity, and involves mitochondria-dependent apoptotic cascades, p38 and c-Jun NH(2)-terminal kinase.
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PMID:5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNF{alpha}-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling. 1751 5

Deregulated signaling by the epidermal growth factor receptor family of proteins is encountered in human malignancies including breast cancer. Cell cycle and apoptosis-regulatory protein-1 (CARP-1), a novel, perinuclear phosphoprotein, is a regulator of apoptosis signaling by epidermal growth factor receptors. CARP-1 expression is diminished in human breast cancers, and correlates inversely with human breast cancer grades which could be attributed to increased methylation. The expression of CARP-1, on the other hand, interferes with the ability of human breast cancer cells to invade through the matrigel-coated membranes, to form colonies in the soft agar, and to grow as s.c. tumors in severe combined immunodeficiency (SCID) mice. To test whether CARP-1 is a suppressor of human breast cancer growth, we generated transactivator of transcription (TAT)-tagged CARP-1 peptides. Treatment of human breast cancer cells with affinity purified, TAT-CARP-1 1-198, 197-454, and 896-1150 peptides caused inhibition of human breast cancer cell proliferation and elevated apoptosis. In contrast, TAT-tagged enhanced green fluorescent protein or CARP-1 (1-198(Y192/F)) peptide failed to inhibit cell proliferation or induce apoptosis. Apoptosis by CARP-1 peptides, with the exception of CARP-1 (1-198(Y192/F)), involves the activation of p38 stress-activated protein kinase and caspase-9. Moreover, administration of TAT-CARP-1 (1-198), but not TAT-tagged enhanced green fluorescent protein or TAT-CARP-1 (1-198(Y192/F)), inhibits growth of human breast cancer cell-derived tumor xenografts in SCID mice. We conclude that CARP-1 is a suppressor of human breast cancer growth, and its expression is diminished in tumors, in part, by methylation-dependent silencing.
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PMID:Transactivator of transcription-tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo. 1751 14

With an increasing cancer rate worldwide, there is an urgent quest for the improvement of anticancer drugs. One of the main problems of present chemotherapy in treatment of tumor patients is the toxicity of drugs. Most of the existent anticancer drugs, unfortunately, attack also proliferating normal cells. In recent years, traditional Chinese herbal remedies have gradually gained considerable attention as a new source of anticancer drugs. Although their healing mechanisms are still largely unknown, some of the drugs have been used to help cancer patients fight their disease at reduced side effects compared to other treatments. In our study, we show that Rocaglamide (Roc), derived from the traditional Chinese medicinal plants Aglaia, induces apoptosis through the intrinsic death pathway in various human leukemia cell lines and in acute lymphoblastic leukemia, chronic myeloid leukemia and acute myeloid leukemia cells freshly isolated from patients. Investigation of the molecular mechanisms by which Roc kills tumors revealed that it induces a consistent activation of the stress-response mitogen-activated protein kinase (MAPK) p38 accompanied with a long-term suppression of the survival MAPK extracellular signal-regulated kinase. These events affect proapoptotic Bcl-2 family proteins leading to depolarization of the mitochondrial membrane potential and trigger caspase-mediated apoptosis involving caspase-9, -8, -3 and -2. Importantly, Roc shows no effects on MAPKs in normal lymphocytes and therefore has no or very low toxicity on healthy cells. Up to now, more than 50 different Roc derivatives have been isolated from Aglaia. Our study suggests that Roc derivatives may be promising candidates for the development of new drugs against hematologic malignancies.
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PMID:The traditional Chinese herbal compound rocaglamide preferentially induces apoptosis in leukemia cells by modulation of mitogen-activated protein kinase activities. 1756 40

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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