Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor cells up-regulate glycolysis but convert pyruvate into lactate instead of oxidizing it. Here, we show that pyruvate, but not lactate, is an inhibitor of histone deacetylases (HDAC) and an inducer of apoptosis in tumor cells and that SLC5A8, a Na(+)/monocarboxylate cotransporter, is obligatory for this process. We found that SLC5A8 is expressed in nontransformed breast epithelial cell lines but silenced by DNA methylation in tumor cell lines. The down-regulation of the gene is also evident in primary breast tumors. When MCF7 breast tumor cells are transfected with SLC5A8 cDNA, the cells undergo pyruvate-dependent apoptosis. Butyrate and propionate also induce apoptosis in SLC5A8-expressing cells, whereas lactate does not. The differential ability of these monocarboxylates to cause apoptosis in SLC5A8-expressing MCF7 cells correlates with their ability to inhibit HDACs. Apoptosis induced by SLC5A8/pyruvate in MCF7 cells is associated with up-regulation of p53, Bax, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), TRAIL receptor (TRAILR) 1, and TRAILR2 and down-regulation of Bcl2 and survivin. Lactate dehydrogenase isozymes are differentially expressed in nontransformed cells and tumor cells such that the latter convert pyruvate into lactate. Silencing of SLC5A8 coupled with conversion of pyruvate into lactate in tumor cells correlates with increased HDAC activity in these cells compared with nontransformed cells. Our studies thus identify pyruvate as a HDAC inhibitor and indicate that the Na(+)-coupled pyruvate transport underlies the tumor-suppressive role of SLC5A8. We propose that tumor cells silence SLC5A8 and convert pyruvate into lactate as complementary mechanisms to avoid pyruvate-induced cell death.
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PMID:SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases. 1717 45

Heat shock protein 70 (Hsp70) is a well-known inhibitor of apoptotic pathways; however, a role for Hsp70 in the modulation of death receptor-mediated apoptosis remains largely unexplored. In this study, the ability of Hsp70 to modulate tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis was examined in SW480 and CCRF-CEM cells. These lines exhibit the characteristics of type I cells (SW480, human colon adenocarcinoma), with no requirement for mitochondrial involvement to exhibit apoptosis following death receptor engagement and type II cells (CCRF-CEM, human leukemic T cell), which do require amplification of the signal through the mitochondria. Unexpectedly, expression of Hsp70 in the type II CCRF-CEM cells enhanced the extent of TRAIL-induced apoptosis, but in SW480, Hsp70 had no impact on TRAIL-induced apoptosis. The enhanced TRAIL-induced apoptosis was accompanied by an up-regulation of TRAIL receptors, R1 and R2, at the cell surface as determined by flow cytometry and at the transcriptional level as assessed by real-time polymerase chain reaction (PCR). Increased expression of Hsp70 led to up-regulated expression of p53, and chromatin immunoprecipitation combined with real-time PCR revealed increased binding of p53 to its consensus sequence in the TRAIL-R2 gene. In contrast, expression of Hsp70 in SW480 cells did not increase p53 or TRAIL-R1 or TRAIL-R2 surface expression. This result is in marked contrast to most apoptotic stresses, including TNFalpha and Fas ligand, where Hsp70 has been shown to inhibit apoptosis in type II cells. These findings suggest that in tumors retaining functional p53 and expressing high levels of Hsp70, TRAIL may be an effective therapy.
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PMID:TRAIL-induced apoptosis is enhanced by heat shock protein 70 expression. 1727 83

Mutations in p53 are the most common genetic abnormality in cancers. Arsenic trioxide (ATO) is an effective chemotherapeutic agent for the treatment of acute promyelocytic leukemia (APL) and is being tested in phase II studies in various types of cancers. We have shown that ATO is a potent inducer of apoptosis in multiple myeloma cells, engaging primarily the intrinsic apoptotic pathway in cells expressing w.t. p53 and the extrinsic apoptotic pathway in cells expressing mutant p53. To further establish the differential apoptotic signals of ATO in relation to p53 functional status we studied the activation of the intrinsic and the extrinsic apoptotic pathways in IM9 myeloma cells expressing w.t. p53 following silencing of p53 and p21 with the corresponding SiRNAs-GFP constructs. In untransfected cells or in cells transfected with GFP-empty vector construct we observed weak apoptosis concomitant with mild depolarization of mitochondrial membrane, depletion of reduced glutathione and release of cytochrome c. Following silencing of p53 or p21 we observed extensive apoptosis concomitant with extensive depolarization of mitochondrial membrane and depletion of reduced glutathione. We also observed in these cells activation of the extrinsic apoptotic pathway through upregulation of APO2/TRAIL and APO2/TRAIL-R2, activation of caspase 8, degradation of FLIP-L and release of apoptosis inducing factors from mitochondria, instead of cytochrome c. In addition, we observed marked activation of the MAP kinase pathway and dephosphorylation of Akt in p53 or p21 silenced cells. Hence, silencing of p53 or p21 in IM9 myeloma cells results in diversion of apoptosis to the extrinsic pathway and sensitization of myeloma cells to ATO.
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PMID:Arsenic trioxide induces p53-dependent apoptotic signals in myeloma cells with SiRNA-silenced p53: MAP kinase pathway is preferentially activated in cells expressing inactivated p53. 1733 40

To potentiate the response of acute myeloid leukemia (AML) to TRAIL cytotoxicity, we have adopted a strategy of combining nutlin-3, a potent non-genotoxic activator of the p53 pathway, with recombinant TRAIL. The rationale for using such a combination was that deletions and/or mutations of the p53 gene occur in only 5-10% of AML and that TRAIL and nutlin-3 activate the extrinsic and intrinsic pathways of apoptosis, respectively. TRAIL induced a rapid increase of apoptosis when added to OCI M4-type and MOLM M5-type AML cells, carrying a wild-type p53, as well as to NB4 M3-type AML, carrying a mutated p53. On the other hand, the small molecule activator of the p53 pathway nutlin-3 induced p53 accumulation, cell cycle arrest and a slow progressive increase of apoptosis in OCI and MOLM but not in NB4. Of note, nutlin-3 up-regulated the surface expression of TRAIL-R2 and synergized with TRAIL in inducing apoptosis in OCI and MOLM as well as in primary M4-type and M5-type AML blasts, but not in NB4 cells. Moreover, while nutlin-3 up-regulated the expression of cyclin dependent kinase inhibitor p21, a p53-target gene mediating cell cycle block and showing anti-apoptotic activity, the simultaneous addition of TRAIL plus nutlin-3 induced the caspase-dependent cleavage of p21. The relevance of p21 down-regulation for sensitizing AML cells to apoptosis was underscored in knocking-down experiments with small interfering RNAs. Our data suggest that the combined treatment of nutlin-3 plus TRAIL might offer a novel therapeutic strategy for AML.
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PMID:Synergistic cytotoxic activity of recombinant TRAIL plus the non-genotoxic activator of the p53 pathway nutlin-3 in acute myeloid leukemia cells. 1750 27

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

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in malignant cells by binding to the death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5). Several agents that therapeutically exploit this phenomenon are being developed. We investigated the anticancer activity of two novel, highly specific agonistic monoclonal antibodies to TRAIL-R1 (mapatumumab, HGS-ETR1) and TRAIL-R2 (lexatumumab, HGS-ETR2) in colon cancer cell lines. Our analyses revealed that colon cancer cells display significantly higher surface expressions of TRAIL-R2 than TRAIL-R1, and are more sensitive to lexatumumab-induced apoptosis. The proapoptotic effects of lexatumumab in TRAIL-resistant HCT8 and HT29 cells were dramatically augmented by the histone deacetylase inhibitors trichostatin A or suberoylanilide hydroxamic acid. The presence of p21, but not p53, was critical for the synergy between lexatumumab and histone deacetylase inhibitors. The absence of p21 did not interfere with the formation of the death-inducing signaling complex by lexatumumab, suggesting the involvement of other apoptotic and/or cell cycle regulators. Indeed, treatment with suberoylanilide hydroxamic acid greatly reduced the expression of the inhibitor of apoptosis protein survivin and cdc2 activity in HCT116 p21(+/+) cells but not in the HCT116 p21(-/-) cells. Inhibition of cdc2 activity with flavopiridol decreased survivin expression and sensitized the p21-deficient cells to lexatumumab-induced apoptosis. Similarly, small interfering RNA-mediated knockdown of survivin also enhanced lexatumumab-mediated cell death. Therefore, survivin expression plays a key role in lexatumumab resistance, and reducing survivin expression by inhibiting cdc2 activity is a promising strategy to enhance the anticancer activity of lexatumumab.
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PMID:Histone deacetylase inhibitors enhance lexatumumab-induced apoptosis via a p21Cip1-dependent decrease in survivin levels. 1763 11

We investigated the effect of a novel histone deacetylase inhibitor, A-423378.0, on the colon carcinoma cell line HCT116 and genetically modified derivatives lacking either p21(cip1/waf1) or p53. HCT116 cell lines were incubated with A-423378.0 at different concentrations for 3-120 h. Cell viability, proliferation and apoptosis rates were determined and verified by western blot, detection of mitochondrial membrane potential breakdown DeltaPsi(m), activation of caspases-3, -8 and cytokeratin 18 cleavage. A subcutaneous xenograft model was established in NMRI mice with daily intraperitoneal injections of 10 mg/kg for 14 days. All three HCT116 cell lines responded to A-423378.0 treatment in a dose- and time-dependent manner via induction of apoptosis as measured by breakdown of DeltaPsi(m) and BrdU incorporation. We identified that A-423378.0 induced the expression of TRAIL and TRAIL receptor, especially TRAIL-R2/hDR5, which was up-regulated in HCT116 cells after treatment with A-423378.0. In vivo, a growth inhibitory effect was observed with HDAC-I treatment, which was paralleled by a down-regulation of PCNA and a concomitant induction of apoptosis. Treatment of wild-type or knock-out HCT116 cells with A-423378.0 exerts potent anti-proliferative and pro-apoptotic effects in vitro and in vivo. A-423378.0 was able to induce apoptosis in both p21(WAF1) and p53 deficient tumour cells, which appeared to be mediated by the intrinsic cell death pathway. Interestingly, the effects of A-423378.0 on the extrinsic cell death pathway through activation of TRAIL and its signalling pathway indicate that A-423378.0 may be a potent new therapeutic compound for the treatment of advanced colorectal cancer.
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PMID:Differential response of p53 and p21 on HDAC inhibitor-mediated apoptosis in HCT116 colon cancer cells in vitro and in vivo. 1798 66

We have investigated the effect of combined treatment with CpG-oligodeoxynucleotide (CpG-ODN) plus Nutlin-3, a small molecule inhibitor of the murine double minute 2/p53 interaction, on the immune activation, cell cycle progression, and apoptosis of peripheral blood B chronic lymphocytic leukemia (B-CLL) cells. CpG-ODN induced a robust up-regulation of immune activation markers (CD54, CD69, CD80, CD86, MHC-II) in Zap70high and Zap70low B-CLL samples. Although cotreatment of B-CLL cells with CpG-ODN + Nutlin-3 did not interfere with such immune activation, CpG-ODN potentiated the Nutlin-3-mediated induction of the death receptors CD95 and TRAIL receptor 2. Importantly, treatment with CpG-ODN did not interfere with the ability of Nutlin-3 to inhibit cell cycle progression and to induce apoptosis. Thus, a therapeutic regimen including CpG-ODN plus Nutlin-3 might have the advantage to preserve the immune activation of B-CLL cells while restraining the prosurvival/proliferative potential of CpG-ODN treatment.
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PMID:Combined treatment of CpG-oligodeoxynucleotide with Nutlin-3 induces strong immune stimulation coupled to cytotoxicity in B-chronic lymphocytic leukemic (B-CLL) cells. 1851 45

We have compared the cytotoxic/cytostatic responses of the SKW6.4 lymphoblastoid B-cells to the alkylating agent chlorambucil, the purine analog fludarabine, the non-genotoxic activator of the p53 pathway, Nutlin-3, used alone or in association with the death-inducing ligand recombinant TRAIL. Exposure to chlorambucil, fludarabine, and Nutlin-3 induced p53 accumulation and variably affected cell cycle progression in SKW6.4 lymphoblastoid cells. In particular, chlorambucil induced cell cycle accumulation at the G2/M checkpoint; Nutlin-3 induced early cell cycle arrest at the G1/S checkpoint, while fludarabine showed an intermediate behavior. On the other hand, recombinant TRAIL alone did not affect cell cycle progression but induced a rapid increase of apoptosis. Analysis of the gene expression profile of the p53-transcriptional targets showed distinct features between chlorambucil, Nutlin-3 and fludarabine, which likely account for their differential effect on cell cycle in SKW6.4 cells. In particular, chlorambucil upregulated the steady-state mRNA expression of SFN/14-3-3sigma, a gene involved in G2/M cell cycle arrest. Of note, all agonists upregulated TRAIL-R2 expression in SKW6.4 cells both at the mRNA and protein levels. Consistently, pretreatment with chlorambucil, fludarabine and Nutlin-3 enhanced SKW6.4 sensitivity to TRAIL-mediated apoptosis.
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PMID:Differential effects of chemotherapeutic drugs versus the MDM-2 antagonist nutlin-3 on cell cycle progression and induction of apoptosis in SKW6.4 lymphoblastoid B-cells. 1809 40

Manipulation of TRAIL receptor 2 (DR5) pathway is a promising therapeutic strategy to overcome TRAIL-resistant lung cancer cells. Preclinical studies have shown that proteasome inhibitors enhance TRAIL-induced apoptosis in lung cancer cells, but the underlying mechanism has not been fully elucidated. In this study, we demonstrated the enhancement of TRAIL-mediated apoptosis in human alveolar epithelial cells by proteasome inhibitors that up-regulate DR5 expression. This effect was blocked by DR5-neutralizing Ab. Using reporter assay, we demonstrated that the p53 and NF-kappaB elements on the DR5 first intron region were involved in proteasome inhibitor-induced DR5 expression. Both p53 small interfering RNA and NF-kappaB inhibitor suppressed DR5 expression, strengthening the significance of p53 and NF-kappaB in DR5 transcription. The protein stability, Ser(392) phosphorylation and Lys(373)/Lys(382) acetylation of p53 were enhanced by MG132. In addition to p53, IkappaBalpha degradation and NF-kappaB translocation was also observed. Moreover, the binding of p53 and p65 to the first intron of DR5 was demonstrated by DNA affinity protein-binding and chromatin immunoprecipitation assays. Intracellular reactive oxygen species (ROS) generation after MG132 treatment contributed to p53, but not p65 nuclear translocation and DNA-binding activity. ROS scavenger dramatically inhibited the apoptosis induced by proteasome inhibitors plus TRAIL. The p53-null H1299 cells were resistant to proteasome inhibitor-induced DR5 up-regulation and enhancement of TRAIL-induced apoptosis. These findings reveal that proteasome inhibitor-mediated NF-kappaB and ROS-dependent p53 activation are contributed to intronic regulation of DR5 transcription, and resulted in the subsequent enhancement of TRAIL-induced apoptosis in human lung cancer cells.
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PMID:Proteasome inhibitors enhance TRAIL-induced apoptosis through the intronic regulation of DR5: involvement of NF-kappa B and reactive oxygen species-mediated p53 activation. 1852 66


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