Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have demonstrated that several splice variants are derived from both the caspase 9 and Bcl-x genes in which the Bcl-x splice variant, Bcl-x(L) and the caspase 9 splice variant, caspase 9b, inhibit apoptosis in contrast to the pro-apoptotic splice variants, Bcl-x(s) and caspase 9. In a recent study, we showed that ceramide induces the dephosphorylation of SR proteins, a family of protein factors that regulate alternative splicing. In this study, the regulation of the alternative processing of pre-mRNA of both caspase 9 and Bcl-x(L) was examined in response to ceramide. Treatment of A549 lung adenocarcinoma cells with cell-permeable ceramide, D-e-C(6) ceramide, down-regulated the levels of Bcl-x(L) and caspase 9b mRNA and immunoreactive protein with a concomitant increase in the mRNA and immunoreactive protein levels of Bcl-x(s) and caspase 9 in a dose- and time-dependent manner. Pretreatment with calyculin A (5 nm), an inhibitor of protein phosphatase-1 (PP1) and protein phosphatase 2A (PP2A) blocked ceramide-induced alternative splicing in contrast to okadaic acid (10 nm), a specific inhibitor of PP2A at this concentrations in cells, demonstrating a PP1-mediated mechanism. A role for endogenous ceramide in regulating the alternative splicing of caspase 9 and Bcl-x was demonstrated using the chemotherapeutic agent, gemcitabine. Treatment of A549 cells with gemcitabine (1 microm) increased ceramide levels 3-fold via the de novo sphingolipid pathway as determined by pulse labeling experiments and inhibition studies with myriocin (50 nm), a specific inhibitor of serine palmitoyltransferase (the first step in de novo synthesis of ceramide). Treatment of A549 cells with gemcitabine down-regulated the levels of Bcl-x(L) and caspase 9b mRNA with a concomitant increase in the mRNA levels of Bcl-x(s) and caspase 9. Again, inhibitors of ceramide synthesis blocked this effect. We also demonstrate that the change in the alternative splicing of caspase 9 and Bcl-x occurred prior to apoptosis following treatment with gemcitabine. Furthermore, doses of D-e-C(6) ceramide that induce the alternative splicing of both caspase 9 and Bcl-x-sensitized A549 cells to daunorubicin. These data demonstrate a role for protein phosphatases 1 (PP1) and endogenous ceramide generated via the de novo pathway in regulating this mechanism. This is the first report on the dynamic regulation of RNA splicing of members of the Bcl-2 and caspase families in response to regulators of apoptosis.
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PMID:De novo ceramide regulates the alternative splicing of caspase 9 and Bcl-x in A549 lung adenocarcinoma cells. Dependence on protein phosphatase-1. 1180 2

Gemcitabine is a relatively new agent with promising activity in solid tumors. Few data are available regarding mechanisms of resistance to gemcitabine downstream from the drug-target interaction. The present study was performed to gain insight into the role of p53 status on the cytotoxicity of gemcitabine on cancer cells. Drug sensitivity, drug metabolism, cell kinetics and drug-induced apoptosis were compared in 2 lines derived from the mammary adenocarcinoma MCF-7: the wildtype p53 (wt-p53) containing MN-1 cell line and, the MDD2 line containing a dominant negative variant of the p53 protein (mut-p53). The MDD2 cell line was significantly more resistant to gemcitabine cytotoxicity than the MN-1 cell line. The resistant phenotype could not be attributed to a defective gemcitabine activation/degradation pathway or altered levels of expression of intracellular targets. Although both cell lines exhibited p53 accumulation, MN-1 but not MDD2 cells, displayed p21(WAF1) induction after exposure to gemcitabine. Gemcitabine induced an S-phase arrest in both cell lines. A more pronounced block in G1 phase, however, was observed in MN1 cells. Exposure to gemcitabine induced a higher degree of apoptosis in MN-1 than in MDD2 cells. This corresponded with suppression of Bcl-2 and Bcl-X/L expression in wt-p53 cells exposed to gemcitabine whereas Bcl-2 levels remained stable and Bcl-X/L levels increased in mut-p53 cells exposed to gemcitabine. We conclude that the p53 status of cancer cells influences their sensitivity to gemcitabine cytotoxicity. Our evidence suggests that loss of p53 function leads to loss of cell cycle control and alterations in the apoptotic cascade, conferring resistance to gemcitabine in cancer cell lines displaying a mut-p53.
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PMID:Expression of a non-functional p53 affects the sensitivity of cancer cells to gemcitabine. 1180 4

Pancreatic cancer is often resistant to conventional chemotherapy. In this study, we examined the role of adenovirus-mediated overexpression of E2F-1 in inducing apoptosis and increasing the sensitivity of pancreatic cancer cells to chemotherapeutic agents. MIA PaCa-2 pancreatic head exocrine adenocarcinoma cells (mutant p53) were treated by mock infection or adenoviruses expressing beta-galactosidase or E2F-1 (Ad-E2F-1) alone or in combination with sublethal concentrations of each chemotherapeutic drug. Cell growth and viability were assessed at selected time points. Apoptosis was evaluated by flow cytometry, characteristic changes in cell morphology and poly (ADP-ribose) polymerase (PARP) cleavage. Western blot analysis was used to examine the expression of E2F-1 and Bcl-2 family member proteins and PARP cleavage. Western blot analysis revealed marked overexpression of E2F-1 at a multiplicity of infection (MOI) of 20 and 70. By 3 days after infection, Ad-E2F-1 treatment at an MOI of 70 resulted in approximately a 20-fold reduction in cell growth and 60% reduction in cell viability as compared to mock-infected cells. Cell cycle analysis, PARP cleavage and changes in cell morphology supported apoptosis as the mechanism of cell death in response to E2F-1. In order to test the efficacy of treatment with a combination of gene therapy and chemotherapy, we utilized concentrations of Ad-E2F-1 which reduced viability to 50% in combination with each chemotherapeutic agent. Cotreatment of the cells with E2F-1 virus and roscovitine (ROS) or etoposide resulted in an additive effect on cell growth inhibition and induction of apoptosis. Interestingly, 5-fluorouracil did not cooperate with Ad-E2F-1 in the mediation of tumor death or inhibition of cell growth. Immunoblotting for Bcl-2 family members revealed no significant changes in the expression levels of Bcl-2, Bcl X(L), Bax or Bak following gene or 'chemogene' therapy with E2F-1. However, a Bax cleavage product was noted which was substantially increased by cotreatment with ROS or etoposide. E2F-1 overexpression initiates apoptosis and suppresses growth in pancreatic MIA PaCa-2 cells in vitro. E2F-1-mediated apoptosis was not associated with significant changes in the expression of Bcl-2 family member proteins in these pancreatic cancer cells. ROS and etoposide, when combined with E2F-1 overexpression, induce apoptosis in an additive manner. This chemogene combination may provide a potentially useful therapeutic strategy for advanced pancreatic cancer.
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PMID:E2F-1 gene therapy induces apoptosis and increases chemosensitivity in human pancreatic carcinoma cells. 1206 45

Grape seed proanthocyanidins have been reported to possess a broad spectrum of pharmacological and medicinal properties against oxidative stress. We have demonstrated that IH636 proanthocyanidin extract (GSPE) provides excellent protection against free radicals in both in vitro and in vivo models. GSPE had significantly better free radical scavenging ability than vitamins C, E and beta-carotene and demonstrated significant cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal cells. GSPE protected against tobacco-induced apoptotic cell death in human oral keratinocytes and provided protection against cancer chemotherapeutic drug-induced cytotoxicity in human liver cells by modulating cell cycle/apoptosis regulatory genes such as bcl2, p53 and c-myc. Recently, the bioavailability and mechanistic pathways of cytoprotection by GSPE were examined on acetaminophen-induced hepatotoxicity and nephrotoxicity, amiodarone-induced pulmonary toxicity, doxorubicin-induced cardiotoxicity, DMN-induced immunotoxicity and MOCAP-induced neurotoxicity in mice. Serum chemistry changes, integrity of genomic DNA and histopathology were assessed. GSPE pre-exposure provided near complete protection in terms of serum chemistry changes and DNA damage, as well as abolished apoptotic and necrotic cell death in all tissues. Histopathological examination reconfirmed these findings. GSPE demonstrated concentration-/dose-dependent inhibitory effects on the drug metabolizing enzyme cytochrome P450 2E1, and this may be a major pathway for the anti-toxic potential exerted by GSPE. Furthermore, GSPE treatment significantly decreased TNFalpha-induced adherence of T-cells to HUVEC by inhibiting VCAM-1 expression. These results demonstrate that GSPE is highly bioavailable and may serve as a potential therapeutic tool in protecting multiple target organs from structurally diverse drug- and chemical-induced toxicity.
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PMID:Cellular protection with proanthocyanidins derived from grape seeds. 1207 78

A role for activins in regulating cellular transformation is suggested by the alpha-inhibin knockout mouse in which development of gonadal tumors is associated with elevated activin levels. It was the purpose of the current study to determine whether activin had similar actions on endometrial cell lines, specifically on a well differentiated estrogen-responsive endometrial adenocarcinoma cell line (ISH) and estrogen-unresponsive cells (HEC-50) obtained from a poorly differentiated endometrial adenocarcinoma. Activin was secreted by both adenocarcinoma cell lines. Using reverse transcription-PCR, messenger RNA type I and type II activin receptor subtypes were detected in both cell lines: expression of IB and IIB was approximately three- to fourfold greater in ISH cells than in HEC-50 cells, while activin receptor IA and IIA messenger RNA levels were approximately equal in both cell lines. Activin treatment (30-300 ng/ml) caused a dose- and time-dependent inhibition of ISH cells proliferation and resulted in a significant decrease in Bcl-2 protein and mRNA levels. No difference was observed in Bax expression. There was no significant effect of activin when the cultures of ISH cells were exposed to 17beta-estradiol. In contrast, activin showed a weak, but significant, mitogenic effect on HEC-50 cells without modifications in Bax and Bcl-2 mRNA and protein levels. The results demonstrate that activin is a regulator of endometrial cancer cell growth. 17beta-Estradiol may promote resistance of estrogen-responsive endometrial cancer cells to the growth-retarding effects of activin and one of the mechanisms might be a down-regulation of the activin receptors.
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PMID:Regulation of endometrial adenocarcinoma cell proliferation by Activin-A and its modulation by 17beta-estradiol. 1208 79

Neurotensin (NT) is a neuropeptide interacting with specific G protein coupled receptors. In the periphery, NT is a hormone of the gastrointestinal tract. The high affinity neurotensin receptor (NT-1 receptor) is over-expressed in a numbers of cancers. Consequently NT growth effects, largely described in normal and adenocarcinomatous tissues, may be of a major importance in tumor proliferation. In this study we demonstrated an anti-apoptotic effect of NT agonist, in the mammary adenocarcinoma cells, MCF-7. Focusing on the cellular events involved, we found an increase in Bcl-2 protein and mRNA levels, resulting in Bcl-2 transcriptional activation, and dependent on MAP kinase pathway.
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PMID:Neurotensin counteracts apoptosis in breast cancer cells. 1215 Sep 75

Trichloroethylene (TCE) and perchloroethylene (PERC) are volatile organic compounds (VOCs) that are primarily inhaled through the respiratory system. The aim of this study was to elucidate the role of glutathione (GSH) and p53 in TCE- and PERC-induced lung toxicity. Human lung adenocarcinoma cells NCI-H460 (p53-wild-type) have constitutively lower levels of GSH than NCI-H1299 (p53-null) cells. The results showed that exposure to vapor TCE and PERC produced a dose-dependent and more pronounced accumulation of H(2)O(2) in p53-WT H460 than p53-null H1299 cells. The accumulation of H(2)O(2) was accompanied by severe cellular damage, as indicated by the significant increase of lipid peroxidation and apoptosis in p53-WT H460 cells, but not p53-null H1299 cells. Cotreatment of p53-WT H460 cells with free radical scavengers, such as D-mannitol, uric acid, and sodium selenite, significantly attenuated the TCE- or PERC-induced lipid peroxidation. In contrast, depletion of GSH in p53-null H1299 cells enhanced TCE- or PERC-induced lipid peroxidation. The levels of p53 and Bax proteins were elevated, while Bcl-2 protein was downregulated in TCE- or PERC-treated p53-WT H460 cells. Activity of caspase 3, the apoptotic executioner, was also significantly enhanced in TCE- or PERC-treated cells. These data suggest that, in human lung cancer cells, GSH plays a vital role in the protection of TCE- and PERC-induced oxidative stress and apoptosis, which may be mediated through a p53-dependent pathway.
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PMID:Possible involvement of glutathione and p53 in trichloroethylene- and perchloroethylene-induced lipid peroxidation and apoptosis in human lung cancer cells. 1216 Sep 29

Recent work suggests that apoptosis is disrupted during the progression of many solid tumors. Isogenic metastatic colon adenocarcinoma cells displayed significantly higher levels of staurosporine-induced apoptosis compared to their nonmetastatic counterparts in vitro. In addition, analysis of 15 matched primary tumors and liver metastases demonstrated that the levels of apoptosis were significantly higher in the metastases, and this increased cell death was associated with significantly lower levels of Bcl-2 protein expression. Our data demonstrate that the molecular events associated with acquisition of the metastatic phenotype sensitize colon cancer cells to some pro-apoptotic stimuli.
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PMID:Increased apoptosis in metastatic human colonic adenocarcinomas. 1219 85

All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.
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PMID:Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax. 1218 56

Barrett's esophagus, or columnar-lined esophagus (CLE), is a premalignant disorder in which the stratified squamous epithelium is replaced by metaplastic epithelium. To gain more insight into the process of carcinogenesis in CLE, we studied several factors involved in the apoptotic pathway in biopsies with gastric metaplasia (GM), intestinal metaplasia (IM), dysplasia, and/or adenocarcinoma. Immunohistochemistry was performed for Fas, Bcl-2, Bax, Bcl-xl, inducible nitric oxide synthase (iNOS), and cyclooxygenase 2 (COX-2). Fas staining was positive in the epithelium of all biopsies from patients with CLE but negative in normal gastric mucosa. Fas staining was positive in all tumor cells of the 8 cases containing adenocarcinoma. Bcl-2 was positive in lamina propria immune cells of all specimens. Bax staining was positive in the epithelium of all biopsies, including tumor cells. Bcl-xl was positive in dysplasia and tumor cells, but negative in 8 of 17 biopsies containing IM. iNOS was positive in 20 of 21 biopsies with IM and in 4 of 8 dysplasia biopsies. COX-2 was positive in 7 of 8 adenocarcinomas. We conclude that the apoptotic balance in the transformation from IM to adenocarcinoma switches to an antiapoptotic phenotype because of increased Bcl-xl expression and decreased Bax expression. Fas can be used as a marker for the differentiation of gastric mucosa and metaplasia in the esophagus. iNOS is highly positive in CLE-associated intestinal metaplasia. COX-2 is negative in nonmalignant CLE. Therefore, pharmacologic inhibition of COX-2 activity is unlikely to be effective in the preventing CLE-associated adenocarcinoma. There was no clear correlation between iNOS expression and activation of proapoptotic and antiapoptotic genes.
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PMID:Expression of apoptosis-related proteins in Barrett's metaplasia-dysplasia-carcinoma sequence: a switch to a more resistant phenotype. 1219 18


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