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: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Therapeutic modalities that overcome the antiapoptotic function of Bcl-2 that is often overexpressed in cancer cells are expected to be a novel strategy for cancer treatment. We previously reported that the leukemic cell death induced by an N-terminally truncated Bax (deltaN Bax: corresponding to amino acid 112-192 of full-length Bax) was not blocked by Bcl-2 or Bcl-x(L) owing to the lack of the BH3 domain needed to interact with the antiapoptotic Bcl-2 family molecules. In this study, we used the Cre-loxP system that allowed us to propagate adenoviruses expressing deltaN Bax, and investigated the effects of the deltaN Bax gene transfer into A549 and NCI-H1299 nonsmall cell lung cancer cell lines. deltaN Bax showed more cell-death-inducing activity in both cells than did the full-length Bax in vitro. It was found that the deltaN Bax-induced cell death was not inhibited by the pan-caspase inhibitor z-VAD-fmk, suggesting that deltaN Bax induces cell death through a caspase-independent mechanism. Intratumoral injection of adenoviruses expressing deltaN Bax into A549 tumors in Balb/c nude mice showed a significantly stronger suppression of tumor growth (74%) than full-length Bax (25%) compared to the control. Our results suggest that deltaN Bax may provide a better alternative than currently used cytotoxic genes in cancer gene therapy trials.
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PMID:N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers. 1273 Jun 79

To form metastases, tumors must break from the primary tumor site, invade surrounding tissues, enter and survive within the circulation and ultimately colonize a distal tissue. Each of these steps requires the cooperative function of numerous proteins--proteins that facilitate angiogenesis (e.g., VEGF), cell survival (e.g., Bcl-2), invasion (e.g., MMPs), and autocrine growth stimulation (e.g., c-myc, cyclin D1). Although expression of these proteins is regulated at many levels by disparate stimuli, translation of these key malignancy-related proteins is regulated primarily by the activity of the mRNA cap-binding protein eIF-4E, the rate-limiting member of the eIF-4F translation initiation complex. By binding the cap structure at the 5' terminus of cellular mRNAs, eIF-4E recruits mRNAs to the eIF-4F complex, which then scans from the 5' cap through the untranslated region (5'UTR), unwinding secondary structure to reveal the translation initiation codon and to enable ribosome loading. Messenger RNAs with short unstructured 5' UTRs are more easily translated than mRNAs harboring lengthy, highly structured 5' UTRs, as these prohibit efficient scanning and start codon recognition. As such, the translation of these mRNAs, which typically encode proteins involved in angiogenesis (e.g., VEGF), tumor growth (cyclin D1) and survival (Bcl-2), is suppressed except when eIF-4E is engaged with the eIF-4F complex--a common event in many human and experimental cancers. This review focuses on the hypothesis that enhanced eIF-4E function contributes to metastatic progression by selectively upregulating the translation of key malignancy-related proteins that together conspire to drive the metastatic process.
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PMID:Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs. 1274 84

Apoptosis is a fundamental biological process used to eliminate unwanted cells in a multicellular organism. An increasing number of regulatory proteins have been identified that either promote or inhibit apoptosis. For tumors to arise, apoptosis must be blocked in the transformed cells, for example by mutational overexpression of anti-apoptotic proteins, which represent attractive target proteins for molecular therapy strategies. In a functional yeast survival screen designed to select new anti-apoptotic mammalian genes, we have identified the chromosomal high-mobility group box-1 protein (HMGB1) as an inhibitor of yeast cell death induced by the pro-apoptotic Bcl-2 family member Bak. The C-terminal 33 amino acids of HMGB1 are dispensable for this inhibitory function. HMGB1 is also able to protect mammalian cells against different death stimuli including ultraviolet radiation, CD95-, TRAIL-, Casp-8-, and Bax-induced apoptosis. We found high HMGB1 protein levels in human primary breast carcinoma. Hmgb1 RNA levels are changing during different stages of mouse mammary gland development and are particularly low during lactation and involution. These data suggest that HMGB1 may participate in the regulation of mammary gland apoptosis and that its high expression level promotes tumor growth because of its anti-apoptotic properties.
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PMID:HMGB1 inhibits cell death in yeast and mammalian cells and is abundantly expressed in human breast carcinoma. 1275 33

It is clear that COX-2 plays an important role in tumor and endothelial cell biology. Increased expression of COX-2 occurs in multiple cells within the tumor microenvironment that can impact on angiogenesis. COX-2 appears to: (a) play a key role in the release and activity of proangiogenic proteins; (b) result in the production of eicosanoid products TXA2, PGI2, PGE2 that directly stimulate endothelial cell migration and angiogenesis in vivo, and (c) result in enhanced tumor cell, and possibly, vascular endothelial cell survival by upregulation of the antiapoptotic proteins Bcl-2 and/or activation of PI3K-Akt. Selective pharmacologic inhibition of COX-2 represents a viable therapeutic option for the treatment of malignancies. Agents that selectively inhibit COX-2 appear to be safe, and well tolerated suggesting that chronic treatment for angiogenesis inhibition is feasible [107-110]. Because these agents inhibit angiogenesis, they should have at least additive benefit in combination with standard chemotherapy [111] and radiation therapy [24, 112]. In preclinical models, a selective inhibitor of COX-2 was shown to potentiate the beneficial antitumor effects of ionizing radiation with no increase in normal tissue cytotoxicity [113-115]. More recently, metronomic dosing regimens of standard chemotherapeutic agents without extended rest periods were shown to target the microvasculature in experimental animal models and result in significant antitumor activity [116-118]. This antiangiogenic chemotherapy regimen could be enhanced by the concurrent administration of an angiogenesis inhibitor [116-119]. Trials that will evaluate continuous low dose cyclophosphamide in combination with celecoxib are underway in patients with metastatic renal cancer, and non-Hodgkin's lymphoma [120]. Given the safety and tolerability of the selective COX-2 inhibitors, and the potent antiangiogenic properties of these agents, the combination of antiangiogenic chemotherapy with a COX-2 inhibitor warrants clinical evaluation [118, 121, 122]. The effects of selective COX-2 inhibitors on angiogenesis may also be due, in part, to COX-independent mechanisms [123-125]. Several reports have confirmed COX-independent effects of celecoxib, at relatively high concentrations (50 microM), where apoptosis is stimulated in cells that lack both COX-1 and COX-2 [126]. More recently, Song et al. [127] described structural modifications to celecoxib that revealed no association between the COX-2 inhibitory and proapoptotic activities of celecoxib [125]. Some of the COX-independent mechanisms for NSAIDs and selective COX-2 inhibitors include activation of protein kinase G, inhibition of NF-kappa B activation, downregulation of the antiapoptotic protein Bcl-XL, inhibition of PPAR delta, and activation of PPAR gamma. One or more of these COX-independent effects could contribute to the antiangiogenic properties of NSAIDs and selective COX-2 inhibitors. In order to take advantage of both the COX-dependent and COX-independent benefits of NSAIDs and selective COX-2 inhibitors, will require evaluation of these agents in neoplastic disease settings, using cancer-specific biomarkers. In conclusion, the contribution of COX-2 at multiple points in the angiogenic cascade makes it an ideal target for pharmacologic inhibition. The reported success of selective COX-2 inhibitors in cancer prevention could be related to angiogenesis inhibition [109]. As premalignant lesions progress towards malignancy, there is a switch to the angiogenic phenotype that is subsequently followed by rapid tumor growth [128, 129]. Intervention with angiogenesis inhibitors at this early stage of carcinogenesis has been shown to attenuate tumor growth in transgenic mouse models [130, 131]. The continued dependence on angiogenesis for later stages of tumorigenesis suggests that COX-2 inhibitors also will have clinical utility in the management of advanced cancers.
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PMID:Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. 1279 55

Archival reports demonstrate that black females are in the minority of reported breast cancer cases, yet are given a significantly poorer prognosis than their white counterparts. Numerous studies have been conducted in an attempt to explain this discrepancy. In the past, socio-economic variables such as economic status and access to adequate health care have been the focus of attention. More recently there has been a shift to understanding the racial differences in genotype, as well as hormones related to tumor growth. In the present report, we explore the effects of increased estrogen levels as a precursor to the detrimental effects of breast cancer in African American women when compared to Caucasian women. Furthermore we will explore the effects of increased estrogen levels on the apoptotic events of p53 and Bcl-2 proteins. We conclude with a discussion regarding the antagonistic behavior of varying isoforms of estrogen receptors, and their relationship to nitric oxide (NO) as a free radical. The main focus of this paper is to address the many carcinogenic pathways that are instigated by estrogen and those which may be linked to obesity. By determining the relative concentration of estrogen and related proteins within black and white populations we hope to better understand the above mentioned disparity.
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PMID:Risk factors for breast cancer and the prognosis of African American women: estrogen's role. 1282 61

Hexokinase II is often highly expressed in poorly differentiated and rapidly growing tumors that exhibit a high rate of aerobic glycolysis. Hexokinase II binds to the mitochondrial membrane through its interaction with the outer membrane voltage-dependent anion channel (VDAC), preferentially at contact sites between the outer and inner mitochondrial membrane. This location is thought to be important for the integration of glycolysis with mitochondrial energy metabolism. VDAC is a critical component of the mitochondrial phase of apoptosis and its interaction with Bcl-2 family proteins controls the rate of release of mitochondrial intermembrane space proteins that activate the execution phase of apoptosis. The proteins involved in the contact sites also constitute the mitochondrial permeability transition, one of the mechanisms by which mitochondrial protein release can be mediated. Hexokinase II binding to VDAC suppresses the release of intermembrane space proteins and inhibits apoptosis, thereby contributing to the survival advantage of tumor cells. This interaction places hexokinase II in a position to integrate glycolytic metabolism of the tumor cell with the control of apoptosis at the mitochondrial level. Mitochondrial binding of hexokinase II may constitute an attractive target for therapeutic intervention to suppress tumor growth.
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PMID:Hexokinase II: the integration of energy metabolism and control of apoptosis. 1287 Nov 25

In this study 65 primary malignant fibrous histiocytomas (MFH) of high malignancy grade were characterized by immunohistochemistry for their expression of proteins reflecting or promoting tumor growth. The results were evaluated in relation to the disease-free survival and the occurrence of metastases alone or in combination with local recurrences during follow-up. A tumor size >8 cm was strongly associated with both a shorter disease-free survival (p=0.001) and a higher frequency of metastases alone or together with local recurrence during follow-up (p=0.001 and 0.004). Similarly a higher frequency of mitosis was associated with a shorter disease-free survival (p=0.004), while the presence of necrosis or malignancy grade 4 did not affect the clinical outcome. No significant effect on the clinical outcome was seen for p53, Ki-67, p27 expression or for vascular density determined by factor VIII staining. However, a significant association was demonstrated between high Bcl2 expression and the risk to develop both local recurrence and metastases (p=0.026). Taken together, the findings support the importance of the tumor size, and suggest that bcl2 staining but not p53, Ki-67, p27, vascular density or distinction of grade 3 and grade 4 tumors are of clinical value in the prognostication of MFH tumors.
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PMID:Evaluation of immunohistochemical parameters as prognostic markers in malignant fibrous histiocytoma. 1288 52

Several signaling pathways have been recognized in normal c-kit-mediated signal transduction following stem cell factor (SCF) stimulation including Janus kinase (JAK)/signal transducer and activator of transcription (STAT), mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3 K) pathways. In gastrointestinal stromal tumor (GIST), c-kit activation is considered to play a central role in its tumorigenesis. However, the signal transduction cascades specific for the SCF-independent c-kit activation in GIST remains to be elucidated. In this study, we examined for the expression of the activated form of STAT3 [phospho-STAT3 (tyr 705)] in eleven cases of GIST by immunohistochemistry. All GISTs had strong nuclear and variable cytoplasmic expression of phospho-STAT3 (tyr 705). Survival and proliferation of two established primary GIST cell lines with c-kit exon-11 mutations were then assessed for their response to inhibitors of c-kit (STI-571), JAK 2 (Tyrphostin AG490), MAPK kinase (PD98059) and PI-3 K(LY294002). GIST cells showed significant inhibition of proliferation and apoptosis when treated with STI571 or AG490 but not in cells treated with PD98059 or LY294002. Bcl-2 was expressed in all of the GIST cases (11 out of 11) and was down-regulated in the primary GIST cells following treatment with AG490. This study demonstrates that STAT3 is constitutively activated in GIST and JAK2 blockade leads to tumor growth inhibition and apoptosis indicating the involvement of the JAK/STAT signaling pathway in GIST cellular survival.
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PMID:Analysis of signal transducer and activator of transcription 3 (STAT3) in gastrointestinal stromal tumors. 1289

Even though we previously reported that dietary lutein can inhibit mammary tumor growth, the mechanism of this action was unknown. Here, we studied the action of dietary lutein through its possible regulation of apoptosis and angiogenesis. Female BALB/c mice were fed a semi-purified diet containing 0 (control), 0.002 or 0.02% lutein (n = 20/treatment) for 2 weeks prior to inoculation with 100,000 -SA mouse mammary tumor cells into the right mammary fat pad. Tumor volume was measured daily until day 50 postinoculation when all mice were killed. Angiogenesis and apoptosis activities in the tumors were measured by immunohistochemistry. Apoptosis and necrosis of blood lymphocytes were quantitated by flow cytometry using Annexin V-FITC and propidium iodide staining. The expression of the p53, Bax and Bcl-2 mRNA was measured by RT-PCR amplification. Lutein was not detectable in the plasma, liver or tumor of unsupplemented mice, but increased in a dose-dependent manner in lutein-supplemented mice. Mice fed lutein had tumors that were 30 to 40% smaller (p < 0.05) on day 50 post-inoculation compared to unsupplemented mice. Final tumor volume was lowest in mice fed 0.002% lutein. Mice fed lutein had higher apoptotic activity in the tumors but lower apoptotic activity in blood lymphocytes as compared to unsupplemented animals. These observations were supported by the observed increase in the expression of the proapoptotic genes, p53 and Bax, together with a decrease in the expression of the antiapoptotic gene, Bcl-2, and consequently an increase in the Bax:Bcl-2 ratio in tumors from lutein-fed mice. Furthermore, lutein-fed mice also had lower (p < 0.05) angiogenic activity in the tumors as compared to unsupplemented mice. The greatest beneficial effect on apoptosis and angiogenesis was observed with mice fed 0.002% lutein. Therefore, dietary lutein, especially at 0.002%, inhibited tumor growth by selectively modulating apoptosis, and by inhibiting angiogenesis.
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PMID:Dietary lutein inhibits mouse mammary tumor growth by regulating angiogenesis and apoptosis. 1292 72

Bcl-2 is a key antiapoptotic protein, and it confers survival advantages on many types of tumors by inhibiting apoptotic cell death. Malignant gliomas are the most common primary central nervous system tumors, but the role of bcl-2 in these tumors has not been defined. We investigated the impact of bcl-2 on malignant gliomas by suppressing its expression. Antisense human bcl-2 cDNA was transfected into human malignant glioma cells. The effects of bcl-2 protein down-regulation on glioma cell morphology, in vitro tumor growth, and tumorigenicity in nude mice, as well as chemosensitivity to cisplatin, were studied. Expression of antisense bcl-2 cDNA decreased bcl-2 protein by more than sixfold. Antisense bcl-2 stable transfectants (AS-bcl-2) showed profound morphological change and markedly retarded cell growth in vitro. Transplantation of AS-bcl-2 cells resulted in no tumor formation, whereas backbone plasmid transfectant control formed tumors in each mouse transplanted. Expression of antisense bcl-2 in glioma cells resulted in significantly increased cytotoxicity of cisplatin. In conclusion, antisense bcl-2 expression can effectively reduce glioma survival, including retarding in vitro growth, complete loss of tumorigenicity, and significantly enhanced cisplatin cytotoxicity. These results suggest that bcl-2 plays an important role in glioma malignancy and chemoresistance. Development of strategies targeted at bcl-2 has the potential to advance treatment for malignant gliomas.
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PMID:Expression of antisense bcl-2 cDNA abolishes tumorigenicity and enhances chemosensitivity of human malignant glioma cells. 1313 May 6


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