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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Little information exists concerning the response of anaplastic thyroid carcinoma (ATC) cells to histone deacetylase inhibitors (HDAIs). In this study, the cellular response to the histone deacetylase inhibitors, sodium butyrate and trichostatin A, was analyzed in cell lines derived from primary anaplastic thyroid carcinomas. HDAIs repress the growth (proliferation) of ATC cell lines, independent of p53 status, through the induction of apoptosis and differential cell cycle arrest (arrested in G1 and G2/M). Apoptosis increases in response to drug treatment and is associated with the appearance of the cleaved form of the caspase substrate, poly-(ADP-ribose) polymerase (PARP). Cell cycle arrest is associated with the reduced expression of cyclins A and B, the increased expression of the cyclin-dependent kinase inhibitors, p21(Cip1/WAF1) and p27Kip1, the reduced phosphorylation of the retinoblastoma protein (pRb), and a reduction in cdk2 and cdk1-associated kinase activities. In ATC cells overexpressing cyclin E, drug treatment failed to replicate these events. These results suggest that growth inhibition of ATC cells by HDAIs is due to the promotion of apoptosis through the activation of the caspase cascade and the induction of cell cycle arrest via a reduction in cdk2- and cdk1-associated kinase activities.
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PMID:Histone deacetylase inhibitors promote apoptosis and differential cell cycle arrest in anaplastic thyroid cancer cells. 1134 29

Cancer chemopreventive effects of inositol hexaphosphate (IP6), a dietary constituent, have been demonstrated against a variety of experimental tumors, however, limited studies have been done against prostate cancer (PCA), and molecular mechanisms are not well defined. In the present study, we investigated the growth inhibitory effect and associated mechanisms of IP6 in advanced human PCA cells. Advanced human prostate carcinoma DU145 cells were used to study the anticancer effect of IP6. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Western immunoblotting, immunoprecipitation and kinase assay were performed to investigate the involvement of G1 cell cycle regulators and their interplay, and end point markers of apoptosis. A significant dose- as well as time-dependent growth inhibition was observed in IP6-treated cells, which was associated with an increase in G1 arrest. IP6 strongly increased the expression of CDKIs (cyclin-dependent kinase inhibitors), Cip1/p21 and Kip1/p27, without any noticeable changes in G1 CDKs and cyclins, except a slight increase in cyclin D2. IP6 inhibited kinase activities associated with CDK2, 4 and 6, and cyclin E and D1. Further studies showed the increased binding of Kip1/p27 and Cip1/p21 with cyclin D1 and E. In down-stream of CDKI-CDK/cyclin cascade, IP6 increased hypophosphorylated levels of Rb-related proteins, pRb/p107 and pRb2/p130, and moderately decreased E2F4 but increased its binding to both pRb/p107 and pRb2/p130. At higher doses and longer treatment times, IP6 caused a marked increase in apoptosis, which was accompanied by increased levels of cleaved PARP and active caspase 3. IP6 modulates CDKI-CDK-cyclin complex, and decreases CDK-cyclin kinase activity, possibly leading to hypophosphorylation of Rb-related proteins and an increased sequestration of E2F4. Higher doses of IP6 could induce apoptosis and that might involve caspases activation. These molecular alterations provide an insight into IP6-caused growth inhibition, G1 arrest and apoptotic death of human prostate carcinoma DU145 cells.
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PMID:Inositol hexaphosphate inhibits growth, and induces G1 arrest and apoptotic death of prostate carcinoma DU145 cells: modulation of CDKI-CDK-cyclin and pRb-related protein-E2F complexes. 1266 18

The effects of synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of human prostate carcinoma PC-3 cells were investigated. Whereas CDCA and UDCA had no effects on the growth of cells in a concentration range we have tested, HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed a weak inhibitory activity. This proliferation-inhibitory effect of the synthetic bile acid derivatives was due to the induction of apoptosis, which was confirmed by observing DNA fragmentation, chromatin condensation and cleavage of PARP. Flow cytometric analysis also revealed that the synthetic bile acid derivatives arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of pRB and enhanced binding of pRB and E2F-1. They also suppressed Cdk2 and cyclin E-dependent kinase activities without changes of their expressions. Furthermore, the synthetic bile acids increased the levels of Cdk inhibitor, p21WAF1/CIP1, expression and activated the reporter construct of p21WAF1/CIP1 promoter in p53-independent manner, and p21WAF1/CIP1 proteins induced by the synthetic bile acid derivatives were associated with Cdk2 and proliferating cell nuclear antigen. These distinctive features suggest that it is possible to create the new drugs useful for cancer therapy from the synthetic bile acid derivatives as lead compounds.
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PMID:Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells. 1296 88

Silymarin, a defined mixture of natural flavonoid, has recently been shown to have potent cancer chemopreventive efficacy against colon carcinogenesis in rat model; however, the mechanism of such efficacy is not elucidated. Here, using pure active agent in silymarin, namely silibinin, we show its antiproliferative and apoptotic effects, and associated molecular alterations in human colon carcinoma HT-29 cells. Silibinin treatment of cells at 50-100 microg/ml doses resulted in a moderate to very strong growth inhibition in a dose- and a time-dependent manner, which was largely due to a G0/G1 arrest in cell cycle progression; higher dose and longer treatment time also caused a G2/M arrest. In mechanistic studies related its effect on cell cycle progression, silibinin treatment resulted in an upregulation of Kip1/p27 and Cip1/p21 protein as well as mRNA levels, and decreased CDK2, CDK4, cyclin E and cyclin D1 protein levels together with an inhibition in CDK2 and CDK4 kinase activities. In other studies, we observed that G2/M arrest by silibinin was associated with a decrease in cdc25C, cdc2/p34 and cyclin B1 protein levels, as well as cdc2/p34 kinase activity. In the studies assessing biological fate of silibinin-treated cells, silibinin-induced cell cycle arrest and growth inhibition were not associated with cellular differentiation, but caused apoptotic death. The quantitative apoptosis analysis showed up to 15% apoptotic cell death after 48 h of silibinin treatment. Interestingly, silibinin-induced apoptosis in HT-29 cells was independent of caspases activation, as all caspases inhibitor did not reverse silibinin-induced apoptosis. This observation was further confirmed by the findings showing a lack in caspases activity increase and caspases and PARP cleavage as well as a lack in cytochrome c release in cytosol following silibinin treatment of HT-29 cells. Additional studies conducted in mice showed that silibinin doses found effective in HT-29 cells are achievable in plasma, which increases the significance of the present findings and their possible translation in in vivo anticancer efficacy of silibinin against colon cancer. Together, these results identify molecular mechanisms of silibinin efficacy as a cell cycle regulator and apoptosis inducer in human colon carcinoma HT-29 cells, and justify further studies to investigate potential usefulness of this nontoxic agent in colon cancer prevention and intervention.
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PMID:Silibinin upregulates the expression of cyclin-dependent kinase inhibitors and causes cell cycle arrest and apoptosis in human colon carcinoma HT-29 cells. 1461 51

The receptor activator of NF-kappaB ligand (RANKL), a recently identified member of the tumor necrosis factor (TNF) superfamily, has been shown to induce osteoclastogenesis and dendritic cell survival. Most members of the TNF superfamily suppress cell proliferation and induce apoptosis, but whether RANKL does so is not known. We demonstrate that treatment of monocyte RAW 264.7 cells with RANKL induces dose-dependent growth inhibition (IC50 = 10 ng/ml) as determined by dye uptake and [3H]thymidine incorporation methods. Suppression of RANKL-induced NF-kappaB activation by dominant-negative IkappaBalpha or by the NEMO-peptide had no effect on RANKL-induced cell growth inhibition. Inhibition of RANKL-induced JNK activation, however, abolished the RANKL-induced apoptosis. Suppression of interaction of RANK with TRAF6 by TRAF6-binding peptide abrogated the anti-proliferative effects of RANKL, suggesting the critical role of TRAF6. Flow cytometric analysis of cells treated with RANKL showed accumulation of cells in G0/G1 phase of the cell cycle, and this accumulation correlated with a decline in the levels of cyclin D1, cyclin D3, and cyclin E and an increase in cyclin-dependent kinase inhibitor p27 (Kip). Flow cytometric analysis showed the presence of annexin V-positive cells in cultures treated with RANKL. RANKL-induced apoptosis was further confirmed using calcein AM/ethidium homodimer-1 dye and cleavage of poly(ADP-ribose) polymerase (PARP), procaspase 3, and procaspase 9; benzyloxycarbonyl-VAD, the pancaspase inhibitor, suppressed the PARP cleavage. Thus, overall, our studies indicate that RANKL can inhibit cell proliferation and induce apoptosis through a TRAF-6-dependent but NF-kappaB-independent mechanism.
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PMID:Evidence that receptor activator of nuclear factor (NF)-kappaB ligand can suppress cell proliferation and induce apoptosis through activation of a NF-kappaB-independent and TRAF6-dependent mechanism. 1464 59

In the present study the deacetylase inhibitor trichostatin A (TSA) was used to elucidate the effect of protein acetylation on cell cycle progression and survival in seven human malignant melanoma cell lines. It was shown that TSA treatment led to a transient G(2)/M phase delay and accumulation of unphosphorylated retinoblastoma protein (pRB) in all cases. TSA significantly induced protein expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) in a dose-dependent manner in all cell lines including those not expressing p21(WAF1/CIP1) constitutively, whereas the levels of both wild-type and mutated p53 protein were reduced. The effect on p53 was not a direct result of inhibition of extracellular signal-regulated kinase-1/2 (ERK1/2) activation by TSA, as treatment of the cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) inhibitor PD98059 did not result in decreased p53 protein level. Furthermore, TSA treatment led to reduction in cyclin D1 whereas cyclin D3 accumulated, the latter due to increased protein stability. Similarly, cyclin A protein was reduced whereas cyclin E level was elevated. The effect on p27(Kip1), CDK4 and CDK2 was only marginal. In all the examined cell lines, TSA treatment resulted in a profound induction of apoptosis and cleavage of poly-(ADP-ribose)-polymerase (PARP) indicative of caspase activity. Similarly, TSA-mediated apoptosis was reversed by the caspase-inhibitor z-vad-fmk. Altogether, these results suggest that p21(WAF1/CIP1) in melanomas is silenced by deacetylation, and furthermore that inhibition of deacetylation may have potential in anticancer therapy of melanoma patients.
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PMID:Deacetylase inhibition in malignant melanomas: impact on cell cycle regulation and survival. 1517 85

Retinoid-related molecules are important potential agents for the treatment of cancer. In the present study, we test the effect of a novel retinoid-related ligand, AGN193198 (4-[3-(1-heptyl-4,4-dimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-3-oxo-prophenyl] benzoic acid), on pancreatic cancer cell proliferation and survival. AGN193198 treatment reduces BxPC-3 cell proliferation more efficiently than high-affinity retinoid acid receptor (RAR)- or retinoid X receptor (RXR)-selective retinoids. Moreover, AGN193198 does not activate transcription from RAR or RXR response elements and its effects on cell survival are not reversed by treatment with RAR- or RXR receptor-selective antagonists. These results suggest that the AGN193198-dependent inhibition of BxPC-3 cell function is not mediated via activation of the classical retinoid receptors. Cell cycle analysis of AGN193198-treated BxPC-3 cells indicates that AGN193198 causes accumulation of cells in G2/M. This change is associated with a marked reduction in regulators of S (cyclin A, cyclin-dependent kinase (cdk)2), G2/M (cyclin B1, cdk1, cdc25c) and G1 (cyclin D1, cyclin E, cdk2, cdk4) phase, and an increase in p21 and p27 level. Kinases assays reveal that cdk1, cdk2 and cdk4 activity are suppressed in AGN193198-treated cells. In addition, reduced cell proliferation is associated with enhanced procaspase (3, 8 and 9) and PARP cleavage. Z-VAD-FMK, a pancaspase inhibitor, inhibits AGN193198-dependent caspase activation and attenuates cell death. Z-VAD-FMK inhibits PARP cleavage, but does not alter the AGN193198-dependent reduction in cell cycle regulatory protein expression and activity, suggesting that caspase activation and suppression of cell cycle regulatory protein levels are independent processes. AGN193198 produces similar responses in other pancreatic cancer cell lines including AsPC-1 and MIA PaCa-2. These studies suggest that AGN193198 may be useful for the treatment of pancreatic cancer.
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PMID:A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis. 1585 29

Proteins of the poly(ADP-ribose) polymerase (PARP) family play a wide array of functions, covering virtually every aspect of DNA metabolism and function, most notably with the response to DNA damage, transcription, and the maintenance of genomic stability. Here we report the identification and characterization of a novel PARP family member, PARP10 (FLJ14464 or hypothetical protein LOC84875). Overexpression of PARP10 results in loss of cell viability, although down-expression by short hairpin RNA leads to delayed G1 progression and concomitant cell death. PARP10 exists in both cytoplasm and nucleus, but only nucleolar PARP10 acquires CDK-dependent phosphorylation through late-G1 to S phase, and from prometaphase to cytokinesis in the nucleolar organizing regions. The PARP activity of PARP10 depends on phosphorylation by CDK2-cyclin E in vitro. CDK-phosphorylated PARP10 is absent in growth-arrested cells. These results suggest that PARP10 functions in cell proliferation and may serve as a marker for proliferating cells.
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PMID:CDK-dependent activation of poly(ADP-ribose) polymerase member 10 (PARP10). 1645 63

(Z)-2-(6-(Thieanisyl-2-yl)hexa-3-en-1,5-diynyl)benzenamine (THDB), an enediyne compound, was identified in our laboratory as a novel antineoplastic agent with broad spectrum of antitumor activities against many human cancer cells. THDB was found to inhibit the growth of HL-60 cells in a time-and dose-dependent manner. Cell cycle analysis showed G2/M phase arrest in HL-60 cells following 48 h exposure to THDB. Analysis of the cell cycle regulatory proteins demonstrated that THDB did not change the steady-state levels of cyclin B1, cyclin E, Cdk1 and Cdc25C, but decreased the protein levels of Cdk2 and cyclin A. THDB also caused a marked increase in apoptosis, as characterized by DNA fragmentation (DNA ladder and sub G1 formation), and poly (ADP-ribose) polymerase (PARP) cleavage, which was associated with activation of caspase-3, caspase-8 and caspase-9. Moreover, the THDB-induced apoptosis was significantly attenuated in the presence of specific inhibitors of caspase-3, -8 and -9. These molecular alterations provide an insight into THDB-caused growth inhibition, G2/M arrest and apoptotic death of HL-60 cells.
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PMID:Induction of G2/M phase arrest and apoptosis by a novel enediyne derivative, THDB, in chronic myeloid leukemia (HL-60) cells. 1706 74

MEK/ERK pathways are frequently activated in acute myelogenous leukemia, and this signal pathway's inhibitor has made it an interesting candidate for cancer chemotherapy. Little is known, however, about the effects of cellular and molecular mechanisms on human leukemic U937 cells. In the present study, we found that treatment with PD98059 significantly arrests the G1 phase through up-regulation of cyclin-dependent kinase (Cdk) inhibitor, and produces morphological features of apoptosis in U937 cells, which were associated with poly(ADP-ribose)polymerase (PARP) cleavage and PLC-gamma1 degradation. PD98059 also decreased the Cdk-2, Cdk-4, cyclin D1, and cyclin E expression, and increased high levels of the mitotic inhibitors p16(INIa), p21(Waf1), and p27(Kip1). Also, Bcl-2's overexpression and a caspase-3 inhibitor z-DEVD-fmk significantly attenuated PD98059-induced apoptosis through the down-regulation of caspase-3 activity, but did not attenuate G1 phase arrest. Moreover, PD98059 down-regulated Akt phosphorylation and produced a synergy effect of apoptosis with LY294002 co-treatment. Thus, our results imply that PD98059-induced apoptosis is significantly involved in down-regulation of Bcl-2, caspase-3 activity, the Akt pathway, and some of the biological functions in U937 cells.
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PMID:PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. 1716 15


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