Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin 13 receptor (IL-13R)-targeted cytotoxin, IL13-PE38QQR, composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE), is found to be highly and specifically cytotoxic to human solid cancer cell lines. However, the mechanism of tumor cell death mediated by IL-13 toxin is still not known. To elucidate the mechanism, we utilized four head and neck cancer cell lines (SCC-25, HN12, KCCT873, and YCUM911), which express high levels of IL-13R, and IL-13 toxin is highly cytotoxic to these cells. We observed chromatin condensation and DNA fragmentation, indicating apoptotic cell death, after treatment with IL-13 toxin, as determined by bis-benzimide staining and DNA ladder assays. However, IL-13 did not induce cell death. Flow cytometric analysis suggested that these cancer cell lines increased the sub-G1/G0 phase DNA population in a dose- and time-dependent manner (ranged between 10 and 30%) after treatment with IL-13 toxin. By Western blot analysis, cleavage of caspase-3 and PARP was observed after treatment with a high concentration of IL-13 toxin, also suggesting apoptotic cell death. In addition, the results of immunofluorescence and RT-PCR assays showed that the apoptosis-regulator, Bcl-2 was downregulated after treatment with IL-13 toxin, while Bax was upregulated. Moreover, significant nitrite production was detected in the HN12 cell line after treatment with IL-13 toxin for 48--96 h. Taken together, our results suggest that IL-13 toxin-induced cytotoxicity is at least partially mediated by the apoptosis and nitric oxide pathways. This information may be useful in developing specific approaches where apoptotic bodies from tumor cells may be used to pulse antigen-presenting cells for immunotherapy of cancer.
 ...
PMID:Apoptotic pathways of cell death induced by an interleukin-13 receptor-targeted recombinant cytotoxin in head and neck cancer cells. 1186 21

We asked whether the constitutive level of DNA strand breaks (SBs) in four human squamous carcinoma cell lines is associated with their radiosensitivity, measured by the clonogenic assay. Because impairment in DNA replication and the action of endogenous deoxyribonucleases are two major sources of DNA strand breaks under normal cell metabolism, we also analyzed DNA polymerase and DNA ligase activities as well as the functional status of Poly(ADP-ribose) polymerase (PARP) and nucleolytic degradation of genomic DNA. We showed that the two relatively radioresistant cell lines, UM-SCC-1 and UT-SCC-5, had a statistically significant lower constitutive level of DNA SBs, as measured by DNA precipitation technique, compared with the two relatively radiosensitive cell lines, UM-SCC-14A and UT-SCC-9. We found that cell lines with a higher level of broken DNA tended to have a higher constitutive level of DNA polymerase alpha activity, measured by incorporation of [(3)H]dTTP in DNase I-activated DNA. UM-SCC-1, UT-SCC-5, and UM-SCC-14A did not show any difference in DNA ligase activity when a nicked oligonucleotide was used as substrate. The most radiosensitive cell line, UT-SCC-9, had a significantly lower ligation efficiency compared to the other three cell lines. The functional status of the PARP was the same in the four cell lines. Although none of the four cell lines showed a characteristic apoptotic or necrotic degradation of genomic DNA, when tested with the "plasmid rejoining assay," a significant degradation of the plasmid DNA in UT-SCC-9 was detected. We conclude that the high fraction of DNA SBs for UT-SCC-9, the most radiosensitive cell line, is most likely a consequence of low ligation efficiency combined with a relatively high DNA polymerase alpha activity and the nuclease degradation of DNA.
 ...
PMID:Radiosensitivity of human squamous carcinoma cell lines is associated with amount of spontaneous DNA strand breaks. 1199 85

We have investigated whether Ginkgo biloba extract (EGb 761) induces apoptosis of oral cavity cancer cells and attempted to characterize the apoptotic pathway activated by EGb 761. The inhibition of SCC 1483 oral cavity cancer cells proliferation was noted from 250 micro/ml of EGb 761. Apoptosis was observed after 24 h of incubation with 250 microg/ml EGb 761 and occurred in a time- and dose-dependent manner. Apoptosis was confirmed by DNA fragmentation and PARP cleavage. Co-treatment with the caspase inhibitor (z-VAD-fmk) inhibited apoptosis and PARP cleavage induced by EGb 761. Caspase-3 activity was upregulated by EGb 761 but reduced to the control level by co-treating with z-VAD-fmk. In summary, EGb 761 induces apoptosis of oral cavity cancer cells and caspase-3 is activated in this apoptosis. Therefore, EGb 761 may be considered as a possible chemopreventive agent against oral cavity cancer.
 ...
PMID:Ginkgo biloba extract (EGb 761) induces apoptosis by the activation of caspase-3 in oral cavity cancer cells. 1579 10

It is unknown whether IL-4 induces apoptosis in oral cavity cancer (OCC) cells and, if so, what the mediator of this apoptosis is. Therefore, this study investigated whether apoptosis of OCC cells is induced by IL-4 and whether 15-lipoxygenase-1 (15-LO-1), induced by IL-4, is the mediator of this apoptosis. SCC 1483 oral cavity cancer cells were used in these experiments, and flow cytometry and PARP cleavage were used to examine apoptosis. At an IL-4 dosage that inhibited 50% of cell proliferation, apoptosis was observed, and this apoptosis was inhibited by 2.2 microM caffeic acid (CA). 15-LO-1 mRNA expression was observed beginning at 8 h after treatment with IL-4, and apoptosis increased after 24 h treatment with IL-4. In this apoptosis, the caspase cascade was not involved. In summary, IL-4 induced apoptosis in SCC 1483 OCC cells, and 15-LO-1, induced by IL-4, may mediate this apoptotic pathway.
 ...
PMID:15-Lipoxygenase-1 induced by interleukin-4 mediates apoptosis in oral cavity cancer cells. 1647 53

The presence of more than one dental alloy in the oral cavity often causes pathological galvanic currents and voltage resulting in superficial erosions of the oral mucosa and eventually in the emergence of oral cancer. In the present study the mechanisms of apoptosis of oral mucosa cancer cells in response to electromagnetic fields was investigated. Direct current (DC) electrical fields with field strengths between 2 and 16 V/m, applied for 24 h to UM-SCC-14-C oral mucosa cancer cells, dose-dependently resulted in decreased cell proliferation as evaluated by Ki-67 immunohistochemistry and upregulation of the cyclin-dependent kinase (CDK) inhibitors p21(cip1/waf1) and p27(kip1), which are associated with cell cycle arrest. Electrical field treatment (4 V/m, 24 h) increased apoptosis as evaluated by immunohistochemical analysis of cleaved caspase-3 and poly-(ADP-ribose)-polymerase-1 (PARP-1). Furthermore, robust reactive oxygen species (ROS) generation, increased expression of NADPH oxidase subunits as well as Hsp70 was observed. Electrical field treatment (4 V/m, 24 h) resulted in increased expression of Cu/Zn superoxide dismutase and decreased intracellular concentration of reduced glutathione (GSH), whereas the expression of catalase remained unchanged. Pre-treatment with the free radical scavenger N-acetyl cysteine (NAC) and the superoxide dismutase mimetic EUK-8 abolished caspase-3 and PARP-1 induction, suggesting that apoptosis in oral mucosa cancer cells is initated by ROS generation in response to DC electrical field treatment.
 ...
PMID:Direct current electrical fields induce apoptosis in oral mucosa cancer cells by NADPH oxidase-derived reactive oxygen species. 1778 77

Exposure to extensive ultraviolet (UV) rays is a major cause of skin cancer, which is thought to be initiated by DNA mutations. Members of the epidermal growth factor receptor (EGFR) family are important in various pathophysiologic processes like cancer and are shown to be phosphorylated upon UV exposure. Here we show that EGFR phosphorylation by modest UV doses is dependent on metalloprotease activity and resultant epidermal growth factor (EGF) family proligand shedding. This proligand cleavage releases the mature ligand, which then binds to and activates EGFR. We show that UV induced EGFR phosphorylation in transformed cell lines of melanocyte and keratinocyte origin, which was reduced upon preincubation with a broad-spectrum metalloprotease inhibitor, BB94. UV also activated EGFR downstream signaling via Erk and Akt pathways in a BB94-sensitive manner. Furthermore, using neutralizing antibodies we found that proligand amphiregulin was required for UV-induced EGFR activation in SCC-9 cells. Using RNAi this EGFR activation was further shown to depend on the metalloproteases ADAM9 and ADAM17 in SCC-9 cells. cDNA array hybridization and RT-PCR analysis showed overexpression of a Disintegrin and a Metalloproteases (ADAMs) and EGF family proligands in melanoma cell lines. Additionally, blocking EGFR signal transactivation by BB94 led to increased apoptosis in UV-irradiated cells. EGFR signal transactivation also led to increased stability of the DNA repair protein, PARP, under UV stress. Thus, both antiapoptotic and DNA repair pathways are activated simultaneously by EGFR signal transactivation. Together, our data provide novel insights into the mechanism of UV-induced EGFR activation, suggesting broad relevance of the UV-ADAM-proligand-EGFR-Erk/Akt pathway and its significance in skin cancer.
 ...
PMID:UV-induced EGFR signal transactivation is dependent on proligand shedding by activated metalloproteases in skin cancer cell lines. 1900 95

EGb 761, extracted from Ginkgo biloba leaves, has been proven to induce caspase-3-dependent apoptosis in oral cavity cancer cells. Since EGb 761 is a composition of various components, it is important to identify which components are responsible for its anticancer effects to reduce the total dosage and to avoid toxicity. Therefore, the study aimed to determine the effective compounds of EGb 761 that induce apoptosis in oral cavity cancer cells and to identify whether caspase-3 was involved in apoptosis of oral cancer cells by EGb 761 components. The results of cell proliferation assays on oral cavity cancer cells showed that kaempferol and quercetin significantly inhibited cellular proliferation at a concentration of 40 microM. Flow cytometry showed that the antiproliferative effects of each component were due to increased apoptosis. Kaempferol and quercetin induced apoptosis in various oral cancer cell lines (SCC-1483, SCC-25 and SCC-QLL1) and showed cleavage of poly (ADP-ribose) polymerase (PARP). Caspase-3 activity assay revealed that induction of apoptosis by kaempferol and quercetin was caspase-3-dependent. In conclusion, the results suggest that kaempferol and quercetin, two components of EGb 761, effectively induce caspase-3-dependent apoptosis of oral cavity cancer cells and can be considered as possible anti-oral cavity cancer agents.
 ...
PMID:Kaempferol and quercetin, components of Ginkgo biloba extract (EGb 761), induce caspase-3-dependent apoptosis in oral cavity cancer cells. 1958 76

The polycomb group (PcG) genes encode a family of proteins that methylate and ubiquitinate histones to close chromatin and suppress gene expression. PcG proteins are present at elevated levels in cancer cells, and this is associated with reduced tumor suppressor protein level and enhanced cell survival. Agents that reduce PcG protein level are regarded as potentially cancer-preventative agents. Sulforaphane (SFN) is a biologically important isothiocyanate found in cruciferous vegetables that is an important candidate chemopreventive agent. However, the impact of SFN on the level and function of PcG proteins in skin cancer cells has not been assessed. We show that SFN treatment causes a concentration-dependent reduction in PcG protein (Bmi-1, Ezh2) expression in SCC-13 skin cancer cells and also reduces trimethylation of lysine 27 of histone H3. This is associated with accumulation of cells in G(2)/M phase; reduced levels of cyclin B1, cyclin A, cyclin dependent kinases 1 and 2; and increased p21(Cip1) expression. Sulforaphane treatment also increases cleavage of procaspase 3, 8, and 9 and enhances PARP cleavage and apoptosis. Similar results are observed in other skin-derived cell immortalized and transformed cell lines. Forced expression of the Bmi-1 polycomb protein in SCC-13 cells reverses these effects. The SFN-dependent loss of Bmi-1 and Ezh2 is due to proteasome-associated degradation. These results suggest that dietary isothiocyanates may suppress cancer progression by reducing PcG protein level via a proteasome-dependent mechanism, thereby inhibiting PcG-dependent pro-survival epigenetic events.
 ...
PMID:Sulforaphane suppresses polycomb group protein level via a proteasome-dependent mechanism in skin cancer cells. 2180 89

TIG3 is a tumor suppressor protein that limits keratinocyte survival during normal differentiation. It is also important in cancer, as TIG3 level is reduced in tumors and in skin cancer cell lines, suggesting that loss of expression may be required for cancer cell survival. An important goal is identifying how TIG3 limits cell survival. In the present study we show that TIG3 expression in epidermal squamous cell carcinoma SCC-13 cells reduces cell proliferation and promotes morphological and biochemical apoptosis. To identify the mechanism that drives these changes, we demonstrate that TIG3 localizes near the centrosome and that pericentrosomal accumulation of TIG3 alters microtubule and microfilament organization and organelle distribution. Organelle accumulation at the centrosome is a hallmark of apoptosis and we demonstrate that TIG3 promotes pericentrosomal organelle accumulation. These changes are associated with reduced cyclin D1, cyclin E and cyclin A, and increased p21 level. In addition, Bax level is increased and Bcl-XL level is reduced, and cleavage of procaspase 3, procaspase 9 and PARP is enhanced. We propose that pericentrosomal localization of TIG3 is a key event that results in microtubule and microfilament redistribution and pericentrosomal organelle clustering and that leads to cancer cell apoptosis.
 ...
PMID:TIG3 tumor suppressor-dependent organelle redistribution and apoptosis in skin cancer cells. 2185 38

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have poor efficacy in head and neck squamous carcinoma cells (HNSCC). Because the IGF-1 receptor (IGF1R) generates potent prosurvival signals and has been implicated in therapeutic resistance, its ability to induce resistance to EGFR-TKIs was studied in vitro. Five HNSCC cell lines showed reduced sensitivity to the EGFR-TKI gefitinib when the IGF1R was activated. In SCC-25 and Cal27 cells, gefitinib inhibited basal and EGF-stimulated EGFR, extracellular signal-regulated kinase (Erk), and Akt phosphorylation and reduced cell number. This correlated with initiation of apoptosis based on a 4-fold increase in PARP cleavage and a 2.5-fold increase in Annexin V positivity. The apoptotic response and reduction in cell number were blocked by IGF1R activation, which resulted in phosphorylation of both Erk and Akt. In both the cell lines, IGF1R-induced Erk, but not Akt, activation was eliminated by gefitinib. IGF1R-induced gefitinib resistance was unaffected by MAP/Erk kinase inhibition with U0126 but was partially impaired by inhibition of phosphoinositide-3-kinase with LY294002. The IGF1R-TKI PQ401 inhibited growth of SCC-25 and Cal27 cells alone and also acted synergistically with gefitinib. Thus, the IGF1R can make HNSCC cells resistant to EGFR-TKI treatment via a prosurvival mechanism. Of the 8 HNSCC tumor samples studied, all samples expressed the IGF1R and 5 showed detectable IGF1R phosphorylation, suggesting that this receptor may be relevant in vivo, and thus, combined EGFR/IGF1R inhibition may be necessary in some patients for effective targeted molecular therapy.
 ...
PMID:Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells. 2187 57


1 2 Next >>