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)

Apoptosis plays a critical role in maintaining genomic integrity by selectively removing the most heavily damaged cells from the population. Reactive oxygen species (ROS) and certain inflammatory cytokines are always elevated during the human carcinogenic process. However, the biological significance of the interplay between ROS and inflammatory cytokine remains elusive. This study demonstrates that interleukin-6 (IL-6) effectively protects gastric cancer cells from the apoptosis induced by hydrogen peroxide (H(2)O(2)). The cell death signaling JNK pathway elicited by H(2)O(2) is also inhibited by IL-6. We further found that Mcl-1, but not other Bcl-2 family members, was up-regulated by IL-6, by a substantial level over 24 h. We further transfected a mcl-1 expression vector, pCMV-mcl-1, into the AGS cells, and successfully obtained several mcl-1-overexpressing clones. Flow cytometric analysis shows that these mcl-1-overexpressing AGS cells are more resistant to the apoptosis induced by H(2)O(2) when compared with the neo control AGS cells. Consistently, the activation of the JNK pathway induced by H(2)O(2) is also blocked in mcl-1-overexpressed cells. These results indicate that the anti-apoptotic effect of IL-6 is, at least in part, due to the up-regulation of mcl-1. To our surprise, either IL-6 exposure or mcl-1 overexpression fails to reduce the level of intracellular peroxides in the AGS cells triggered by H(2)O(2). This study also determined the level of 8-hydroxydeoxyguanosine (8-OH-dGua), an indicator for oxidative DNA lesions in IL-6-treated or mcl-1-overexpressed AGS cells after treatment with H(2)O(2). Notably, our results indicate that a majority of the 8-OH-dGua is efficiently removed in the AGS cells without IL-6 treatment, whereas only approximately 50% of the 8-OH-dGua was repaired in the IL-6-treated AGS cells after 24 h. Similarly, approximately 60-70% of the 8-OH-dGua also failed to repair and was retained in the genomic DNA of the mcl-1 transfectants. Results in this study provide a novel mechanism by which up-regulation of the Mcl-1 protein by IL-6 may enhance the susceptibility to H(2)O(2)-induced oxidative DNA lesions by overriding apoptosis.
Carcinogenesis 2001 Dec
PMID:IL-6 inhibits apoptosis and retains oxidative DNA lesions in human gastric cancer AGS cells through up-regulation of anti-apoptotic gene mcl-1. 1175 24

Although the pharmacological role of beta-carotene in the prevention and treatment of colon cancer has received increasing attention, little is known about the molecular mechanisms of action of this carotenoid. The present study demonstrates that beta-carotene, a natural pigment widely present in fruit and vegetables, inhibits the growth of several human colon adenocarcinoma cell lines (COLO 320 HSR, LS-174, HT-29 and WiDr) by inducing cell cycle arrest in G(2)/M phase and apoptosis. These effects were dose and time dependent and strictly related to cell ability to accumulate the carotenoid. COLO 320 HSR cells incorporated beta-carotene to a greater extent than LS-174, HT-29 and WiDr cells and, concomitantly, they exhibited a higher sensitivity to the growth inhibitory effects of the carotenoid. At inhibitory concentrations beta-carotene reduced the expression of cyclin A, a key regulator of G(2)/M progression. Neither p21 nor p27, two cyclin kinase inhibitors, were significantly modified by carotenoid treatment. With respect to apoptosis induction, decreased levels of the apoptosis blocking proteins Bcl-2 and Bcl-xL were also observed. On the other hand, no changes in expression of the apoptosis promoter protein Bax were detected. This study represents a novel aspect of the biological profile of beta-carotene and a new step in elucidating the underlying molecular mechanisms of its antitumor action. In addition, since cell growth inhibitory effects were reached at beta-carotene concentrations achievable in vivo following its supplementation, this study provides a rational approach for the use of beta-carotene in colon cancer.
Carcinogenesis 2002 Jan
PMID:Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by beta-carotene through down-regulation of cyclin A and Bcl-2 family proteins. 1175 18

Pharmacologically safe compounds that can inhibit the proliferation of tumor cells have potential as anticancer agents. Curcumin, a diferuloylmethane, is a major active component of the food flavor turmeric (Curcuma longa) that has been shown to inhibit the proliferation of a wide variety of tumor cells. The apoptotic intermediates through which curcumin exhibits its cytotoxic effects against tumor cells are not known, and the participation of antiapoptotic proteins Bcl-2 or Bcl-xl in the curcumin-induced apoptosis pathway is not established. In the present report we investigated the effect of curcumin on the activation of the apoptotic pathway in human acute myelogenous leukemia HL-60 cells and in established stable cell lines expressing Bcl-2 and Bcl-xl. Curcumin inhibited the growth of HL-60 cells (neo) in a dose- and time-dependent manner, whereas Bcl-2 and Bcl-xl-transfected cells were relatively resistant. Curcumin activated caspase-8 and caspase-3 in HL-60 neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Similarly, time-dependent poly(ADP)ribose polymerase (PARP) cleavage by curcumin was observed in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. Curcumin treatment also induced BID cleavage and mitochondrial cytochrome c release in neo cells but not in Bcl-2 and Bcl-xl-transfected cells. In neo HL-60 cells, curcumin also downregulated the expression of cyclooxygenase-2. Because DN-FLICE blocked curcumin-induced apoptosis, caspase-8 must play a critical role. Overall, our results indicate that curcumin induces apoptosis through mitochondrial pathway involving caspase-8, BID cleavage, cytochrome c release, and caspase-3 activation. Our results also suggest that Bcl-2 and Bcl-xl are critical negative regulators of curcumin-induced apoptosis.
Carcinogenesis 2002 Jan
PMID:Curcumin (diferuloylmethane) induces apoptosis through activation of caspase-8, BID cleavage and cytochrome c release: its suppression by ectopic expression of Bcl-2 and Bcl-xl. 1175 35

This study examined the role of signal transduction and apoptosis in malignant transformation induced by arsenic. Prior study showed that chronic arsenite exposure (500 nM, > or =18 weeks) induced malignant transformation in rat liver TRL 1215 cells. In the present work, these transformed cells were compared with passage-matched control cells. In addition, TRL 1215 cells were treated subchronically (up to 6 weeks) with arsenic (termed pre-transformed cells) to define events occurring prior to arsenic-induced transformation. Flow cytometry using annexin/FITC revealed that arsenic-induced apoptosis in transformed cells was markedly suppressed in comparison to control or pre-transformed cells. Ro318220, a strong activator of JNK, enhanced arsenite-induced apoptosis in transformed cells. Densitometric analysis of western blots revealed that the ratios of both Bcl-x(L)/Bax and Bcl-2/Bax were significantly increased (>2.5-fold) in arsenic-transformed cells. Transformed, pre-transformed and control cells were treated with arsenic and levels of phosphorylated extracellular signal-regulated kinases, ERK1/2, JNK1/2 and p38 were determined by western blot analysis. The three mitogen-activated protein kinases (MAPKs) were phosphorylated in a dose-dependent fashion in all cell types. However, the levels of phosphorylated JNK1/2 were markedly decreased in the arsenic-transformed cells, whereas in pre-transformed cells the levels of phosphorylated MAPKs remained the same as in control cells. JNK kinase activity was suppressed in transformed cells whereas Ro318220 enhanced this activity. Thus, during arsenic-induced malignant transformation resistance to apoptosis develops, possibly due to perturbation of the JNK pathway.
Carcinogenesis 2002 Jan
PMID:Acquisition of apoptotic resistance in arsenic-induced malignant transformation: role of the JNK signal transduction pathway. 1175 36

AIM:To investigate the chemopreventive effects of green tea and tea pigment on 1,2-dimethylhydrazine (DMH)-induced rat colorectal carcinogenesis.METHODS:Male weaning Wistar rats were randomly allocated into four groups.Rats in the positive control group were given a(c)s.c. injection of DMH, once a week for ten weeks;rats in tea treated groups, with the same DMH treatment as in the positive group, received 2% green tea and 0.1% tea pigments; rats in the negative control group were given s.c.injection of the same volume of saline as well as DMH in the positive group. Animals were sacrified and necropsied at the end of week 16 and week 32.RESULTS:Aberrant cryptic foci (ACF) were formed in animals in DMH-treated groups at the end of week 16. Compared to the DMH group, green tea and tea pigments groups had less ACF (148.25 and 204.25, respectively, P<0.01). At the end of week 32, all rats in DMH group developed large intestinal tumors. The results also showed that DMH increased labeling index (LI) of proliferating cell nuclear antigen (PCNA) of intestinal mucosa and the expression of ras-p21. However, in the tea-treated groups, PCNA-LI was significantly reduced as compared with the positive control group (36.63 and 40.36 in the green tea group and tea pigment group, respectively, at the end of the experiment,P<0.01).ras-p21 expression was also significantly reduced (2.07 and 2.36 in the colon tumors of rats in the green tea group and tea pigments group, respectively at the end of the experiment, P<0.01). Furthermore, green tea and tea pigment inhibited the expression of Bcl-2 protein (2, 5, 1, 0 and 2, 4, 1, 0,respectively, at the end of the experiment P<0.01), and induced expression of Bax protein (0,1,3,4 and 0,1,4,3, respectively, P <0.01).CONCLUSION:Chinese green tea drinking inhibited ACF and colonic tumors formation in rats, which showed that tea had a significant chemopreventive effect on DMH-induced colorectal carcinogenesis. Such effects may be due to suppression of cell proliferation and induction of apoptosis in the intestinal crypts.
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PMID:Chemoprevention of tea on colorectal cancer induced by dimethylhydrazine in Wistar rats. 1181 77

Immunohistochemical studies of regulator proteins p53, Bcl-2, Bax, Ki-67, and CD-95L showed that apoptosis suppression, allowing unlimited proliferation of tumor cells, plays an important role in the carcinogenesis of uveal melanoma. This fact dictates the need of including drugs arresting suppression or inducing apoptosis in therapeutic protocols for uveal melanoma. Prognostic significance of p53, Bcl-2, Bax, and CD-95L was demonstrated. Each of the peptides can be used as a prognostic marker.
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PMID:[Prospects for developing treatment of uveal melanoma from the position of modern carcinogenesis concepts]. 1189 58

We examined p53, p21WAF-1, and Bcl-2 protein expression in malignant and nonmalignant bronchial specimens obtained during bronchoscopy from 60 lung cancer patients. Twenty-six (43.3%), 36 (60%), and 20 (33.3%) of the tumors were p53, p21WAF-1, and Bcl-2 positive, respectively. High-level p53 and Bcl-2 expression characterized advanced preneoplastic lesions, while hyperplasias, squamous metaplasias, and mild dysplasias exhibited low levels of expression. There was no difference between early and advanced preneoplastic lesions in the level of p21WAF-1, expression. A history of heavy smoking was associated with p21WAF-1, expression in preneoplastic lesions (p = 0.022) and tumors (p = 0.032). p53(-)/p21WAF-1(++)/bcl-2(-) was the only significant independent predictor of lower clinical stage (OR: 0.88, p = 0.038). In univariate analysis, survival of NSCLC patients was affected by disease stage (p <0.001) and tumor histology (p = 0.018). While single-protein expression was not associated with prognosis, the combined immunophenotype p53(-)/p21WAF-1(++)/bcl-2(-) predicted longer survival (p = 0.03). In multivariate analysis, only the TNM stage was found to be a prognostic factor for NSCLC. We conclude that p53 and Bcl-2 alterations may happen early in bronchial carcinogenesis and that absence of these alterations in combination with p21WAF-1, overexpression may be associated with a less aggressive tumor behavior.
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PMID:Combined expression of p53, Bcl-2, and p21WAF-1 proteins in lung cancer and premalignant lesions: association with clinical characteristics. 1197 95

Tumor development is thought to require both increased proliferation and inhibition of apoptosis. However, the relationship between cell replication and cell death in liver tumorigenesis is complex because both proliferation and apoptosis increase during hepatocarcinogenesis. To investigate the effect of the anti-apoptotic gene Bcl-2 in liver carcinogenesis, we established a line of double transgenic mice that express transforming growth factor-alpha (TGF-alpha), a liver mitogen, and Bcl-2. Double transgenic mice, TGF-alpha and Bcl-2 single transgenics, and wild type received an injection of diethylnitrosamine at 15 days of age. This alkylating agent induces liver carcinogenesis and its effect is greatly enhanced by TGF-alpha. We report that Bcl-2 expression inhibited diethylnitrosamine-induced liver carcinogenesis and counteracted the enhancing effect of TGF-alpha. Bcl-2 delayed the growth of proliferative foci at the early stages of carcinogenesis and inhibited cell proliferation in these foci. The effect of Bcl-2 on liver carcinogenesis is consistent with its reported ability to interfere with cell replication. The data demonstrate that the expression of an anti-apoptotic gene during liver carcinogenesis causes a delay rather than an increase in tumorigenesis.
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PMID:Bcl-2 expression inhibits liver carcinogenesis and delays the development of proliferating foci. 1200 Jul 6

The exact mechanisms of physiological regeneration and of metaplastic processes of the salivary duct have not been definitely established, although regeneration from a putative uncommitted stem cell population has long been favored. In the present study, double immunohistochemical labeling for Ki 67 and alpha-actin or different cytokeratin subtypes, respectively, made possible an exact localization and quantification of cellular proliferation in the regular salivary duct and in different types of metaplasia. Our data demonstrate a baseline proliferative capacity in all five cell types of the salivary duct. Luminal secretory cells of the acinus and intercalated duct regenerate independently from myoepithelial or basal cells. In contrast, the renewal of oxyphilic cells in the striated and excretory duct is maintained by proliferation and differentiation of basal cells. The great majority of metaplasias develops from uncommitted, Bcl-2 positive basal cells of striated/excretory ducts which possess an enormous capacity for pluridirectional morphogenetic differentiation. Despite this important role of basal cells, our findings demonstrate that all cell types principally have to be considered as potential progenitor cells for salivary gland tumors. The improved insight into regenerative and metaplastic processes of the salivary duct may contribute to a better understanding of the complex formal carcinogenesis.
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PMID:A morphogenetic concept of salivary duct regeneration and metaplasia. 1202 27

Aberrant proliferation is an early-occurring event in vitro prior to tumorigenesis in vivo in the multistep process of carcinogenesis. Inhibition of aberrant proliferation therefore may represent a useful biomarker to evaluate the efficacy of chemopreventive agents. Retinoids have exhibited preventive efficacy in vitro and in vivo predominantly through the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). Clinically relevant biochemical and cellular mechanistic endpoints for chemopreventive effects of retinoids should provide novel biomarkers. The present study was designed to examine the preventive efficacy of natural retinoids, all-trans-retinoic acid (ATRA) and 9-cis-retinoic acid (9cisRA), and to identify the possible mechanisms for their effects using the HER-2/neu oncogene expressing preneoplastic human mammary epithelial 184-B5/HER cells. Seven-day treatment with ATRA and 9cisRA exhibited a dose-dependent growth inhibition. Long-term (21 days) treatment with IC20 doses of 50 nM ATRA and 100 nM 9cisRA inhibited anchorage-dependent colony forming efficiency by about 75.4% (p<0.01) and 84.9% (p<0.01), respectively. Cell cycle analysis revealed that a 24-h treatment with IC90 doses of 2 microM ATRA and 3 microM 9cisRA accumulates cells in the G0/G1 phase and inhibit S and/or G2/M phase of the cell cycle. ATRA and 9cisRA induced an 11-fold (p=0.03) and a 9-fold (p=0.04) increase in subG0/G1 (apoptotic) population relative to the solvent control, respectively. ATRA and 9cisRA induced 77% (p=0.01) and 51% (p=0.02) decrease in tyrosine kinase immunoreactivity, respectively. Similarly, the two retinoids caused almost a 50% (p=0.01) down-regulation of Bcl-2 immunoreactivity. Western blot analysis revealed that ATRA induced an increase in RARbeta expression and a decrease in RARgamma expression, while 9cisRA down-regulated RXRalpha expression. These data demonstrate that ATRA and 9cisRA may inhibit HER-2/neu induced aberrant proliferation in part by retarding cell cycle progression, down-regulating HER-2/neu-mediated signal transduction and inducing Bcl-2-dependent apoptosis through a retinoid receptor-mediated mechanism.
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PMID:Preventive efficacy of receptor class selective retinoids on HER-2/neu oncogene expressing preneoplastic human mammary epithelial cells. 1206 59


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