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)

Although resveratrol, an active ingredient derived from grapes and red wine, possesses chemopreventive properties against several cancers, the molecular mechanisms by which it inhibits cell growth and induces apoptosis have not been clearly understood. Here, we examined the molecular mechanisms of resveratrol and its interactive effects with TRAIL on apoptosis in prostate cancer PC-3 and DU-145 cells. Resveratrol inhibited cell viability and colony formation, and induced apoptosis in prostate cancer cells. Resveratrol downregulated the expression of Bcl-2, Bcl-X(L) and survivin and upregulated the expression of Bax, Bak, PUMA, Noxa, and Bim, and death receptors (TRAIL-R1/DR4 and TRAIL-R2/DR5). Treatment of prostate cancer cells with resveratrol resulted in generation of reactive oxygen species (ROS), translocation of Bax to mitochondria and subsequent drop in mitochondrial membrane potential, release of mitochondrial proteins (cytochrome c, Smac/DIABLO, and AIF) to cytosol, activation of effector caspase-3 and caspase-9, and induction of apoptosis. Resveratrol-induced ROS production, caspase-3 activity and apoptosis were inhibited by N-acetylcysteine. Bax was a major proapoptotic gene mediating the effects of resveratrol as Bax siRNA inhibited resveratrol-induced apoptosis. Resveratrol enhanced the apoptosis-inducing potential of TRAIL, and these effects were inhibited by either dominant negative FADD or caspase-8 siRNA. The combination of resveratrol and TRAIL enhanced the mitochondrial dysfunctions during apoptosis. These properties of resveratrol strongly suggest that it could be used either alone or in combination with TRAIL for the prevention and/or treatment of prostate cancer.
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PMID:Molecular mechanisms of resveratrol (3,4,5-trihydroxy-trans-stilbene) and its interaction with TNF-related apoptosis inducing ligand (TRAIL) in androgen-insensitive prostate cancer cells. 1763 62

Natural products derived from plants provide a rich source for development of new anticancer drugs. Dulxanthone A was found to be an active cytotoxic component in Garcinia cowa by bioactivity-directed isolation. Studies to elucidate the cytotoxic mechanisms of dulxanthone A showed that dulxanthone A consistently induced S phase arrest and apoptosis in the most sensitive cell line HepG2. Furthermore, p53 was dramatically up-regulated, leading to altered expression of downstream proteins upon dulxanthone A treatment. Cell cycle related proteins, such as cyclin A, cyclin B, cyclin E, cdc-2, p21 and p27 were down-regulated. Some apoptosis correlated proteins were also altered following the drug treatment. Bcl-2 family members PUMA was up-regulated while Bcl-2 and Bax were down-regulated. However, the expression ratio of Bax/Bcl-2 was increased. This resulted in the release of cytochrome C from the mitochondria to the cytosol. Concurrently, Apaf-1 was stimulated with p53 by dulxanthone A. In result, cytochrome C, Apaf-1 and procaspase-9 form an apoptosome, which in turn triggered the activation of caspase-9, caspase-3 and downstream caspase substrates. Lamin A/C and PARP were down-regulated or cleaved, respectively. Moreover, cell cycle arrest and apoptosis in HepG2 cells induced by dulxanthone A were markedly inhibited by siRNA knockdown of p53. In summary, dulxanthone A is an active cytotoxic component of G. cowa. It induces cell cycle arrest at lower concentrations and triggers apoptosis at higher concentrations via up-regulation of p53 through the intrinsic mitochondrial pathway in HepG2 cells. Dulxanthone A is therefore likely a promising preventive and/or therapeutic agent against Hepatoma.
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PMID:Dulxanthone A induces cell cycle arrest and apoptosis via up-regulation of p53 through mitochondrial pathway in HepG2 cells. 1784 33

Deregulation of apoptosis is involved in mechanisms of cancer development. PUMA is a pro-apoptotic member of the Bcl-2 family and mediates p53-dependent and -independent apoptosis. The aim of this study was to investigate whether alterations of PUMA protein expression and somatic mutations of PUMA gene are characteristics of human hepatocellular carcinoma (HCC). We analyzed expression of PUMA protein in 20 HCCs using immunohistochemistry. Also, we analyzed mutation of the Bcl-2 homology 3 (BH3) domain of PUMA gene, which is an important domain in apoptosis function of PUMA by single-strand conformation polymorphism (SSCP) in 69 HCCs. PUMA protein expression was detected in both HCC cells and non-tumor hepatocytes in all of the 20 HCCs. In 10 of these HCCs, cancer cells showed higher PUMA expression than non-tumor (cirrhotic) hepatocytes of the same patients; whereas in the remaining 10, cancer cells and non-tumor hepatocytes showed similar levels. Mutational analysis revealed no PUMA BH3 domain mutation in the 69 HCCs, suggesting that PUMA BH3 domain mutation is not a direct target of inactivation in hepatocellular cancer development. The increased expression of PUMA in malignant hepatocellular cells relative to that in non-tumor hepatocytes suggests that PUMA expression may play a role in HCC development.
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PMID:Expressional and mutational analysis of pro-apoptotic Bcl-2 member PUMA in hepatocellular carcinomas. 1793 15

Recent studies in non-neuronal cells have shown that the tumor suppressor p53 can promote cell death through a transcription-independent mechanism involving its direct action with a subset of Bcl-2 family member proteins in the cytosol and at the mitochondria. In cultured cortical neurons, however, we could not find evidence supporting a significant contribution of the cytosolic/mitochondrial p53 pathway, and available evidence instead corroborated the requirement for the transcriptional activity of p53. When directly targeted to the cytosol/mitochondria, wild-type p53 lost its apoptosis-inducing activity in neurons but not in non-neuronal cells. The N-terminal p53 fragment (transactivation and proline-rich domains), which induces apoptosis in non-neuronal cells via the cytosolic/mitochondrial pathway, displayed no apoptogenic activity in neurons. In neuronal apoptosis induced by camptothecin or an MDM2 (murine double minute 2) inhibitor, nutlin-3, endogenous p53 protein did not accumulate in the cytosol/mitochondria, and transcriptional inhibition after p53 induction effectively blocked cell death. In addition, overexpression of a dominant-negative form of p53 (R273H) completely suppressed induction of proapoptotic p53 target genes and cell death. PUMA (p53-upregulated modulator of apoptosis) was one such gene induced by camptothecin, and its overexpression was sufficient to induce Bax (Bcl-2-associated X protein)-dependent neuronal death, whereas Noxa was not apoptogenic. These results collectively demonstrate that, in contrast to non-neuronal cells, the apoptotic activity of p53 in postnatal cortical neurons does not rely on its direct action at the cytosol/mitochondria but is exclusively mediated through its transcription-dependent functions. The uniqueness of p53-mediated apoptotic signaling in postnatal cortical neurons was further illustrated by the dispensable function of the proline-rich domain of p53.
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PMID:Apoptotic actions of p53 require transcriptional activation of PUMA and do not involve a direct mitochondrial/cytoplasmic site of action in postnatal cortical neurons. 1798 86

Head and neck squamous cell carcinoma (HNSCC) ranks the eighth most common cancer worldwide. The patients often present with advanced disease, which responds poorly to chemoradiation therapy. PUMA is a BH3-only Bcl-2 family protein and a p53 target that is required for apoptosis induced by p53 and various chemotherapeutic agents. In this study, we found that PUMA induction by chemotherapeutic agents is abrogated in most HNSCC cell lines. Adenoviral gene delivery of PUMA induced apoptosis and chemosensitization more potently than did adenoviral delivery of p53 in HNSCC cells. Finally, we showed that PUMA suppressed the growth of HNSCC xenograft tumors and sensitized them to cisplatin through induction of apoptosis. Our data suggest that absence of PUMA activation in HNSCC cells contributes to chemoresistance and that gene therapy with PUMA might be an efficient substitute for p53 to enhance the responses of HNSCC cells to chemotherapy.
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PMID:Chemosensitization of head and neck cancer cells by PUMA. 1808 12

The molecular changes involved in the induction of apoptosis by vincristine in melanoma have not yet been well defined. Two human melanoma cell lines showing moderate (Mel-RM) and high (IgR3) sensitivity to vincristine were selected from a panel of eight melanoma lines for analysis. Induction of apoptosis was caspase dependent, and was associated with increases in mitochondrial membrane permeability. Vincristine upregulated the expression of Bax, Bak, PUMA, Noxa, p53 and p21 proteins, and downregulated and/or phosphorylated the Bcl-2 protein. Inhibitors of the Jun N-terminal kinase (JNK), but not p38 mitogen-activated protein kinase, significantly inhibited vincristine-induced apoptosis in both IgR3 and Mel-RM cells. In addition, vincristine induced phosphorylation and reduction in Bcl-2 was prevented by an inhibitor of JNK. Downregulation of mRNA for p53, PUMA or Bim by RNA interference had little or no influence on vincristine-induced apoptosis in IgR3 cells. In addition, silencing Bim mRNA did not affect vincristine-induced apoptosis in Mel-RM cells. These results suggest that vincristine-induced apoptosis of at least some melanoma cell lines is dependent on the activation of JNK. The results are consistent with the phosphorylation of Bcl-2 protein, resulting in the activation of Bax/Bak, release of cytochrome c from the mitochondria and the resulting activation of caspases.
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PMID:Activation of Jun N-terminal kinase is a mediator of vincristine-induced apoptosis of melanoma cells. 1817 16

Semicarbazide sensitive amine oxidase (SSAO) is a multifunctional enzyme present mainly in adipocytes, endothelial and smooth muscle cells. It metabolizes primary aliphatic and aromatic amines generating products able to contribute to cellular oxidative stress. SSAO is expressed in a membrane-bound form and is also present as a soluble enzyme in plasma. Both isoforms are increased in several pathologies, and the catalytic products generated by the soluble enzymatic activity can induce cytotoxicity of vascular cells in culture. We have analyzed whether the transmembrane form of the enzyme is able to produce a cytotoxic effect through methylamine oxidation. Since cells in culture lose the expression of this enzyme, we used an SSAO stably transfected smooth muscle cell line. Herein we report that cell treatment with the substrate methylamine induced a dose and time dependent cytotoxic effect. The tumor suppressor protein p53 played an important role in the molecular pathway involved in this cell death. Moreover, we also observed the induction of PUMA-alpha expression with mitochondrial Bcl-2 family proteins being affected, and final effector caspases being activated.
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PMID:p53 phosphorylation is involved in vascular cell death induced by the catalytic activity of membrane-bound SSAO/VAP-1. 1834 72

The Trp53 tumor suppressor gene product (p53) functions in the nucleus to regulate proapoptotic genes, whereas cytoplasmic p53 directly activates proapoptotic Bcl-2 proteins to permeabilize mitochondria and initiate apoptosis. Here, we demonstrate that both p53 transcription-dependent and -independent pathways contribute to UV-induced apoptosis. First we show that Pifithrin-alpha, a small molecule inhibitor of p53 transcriptional activity, delays Bax translocation and cell death by UV irradiation. Then using CHX (cycloheximide) to prevent new protein expression in response to p53, we also find that Bax translocation and cell death by UV irradiation are delayed. Furthermore we find that overexpression of Bcl-x(L), an inhibitor of cytoplasmic p53 after UV irradiation, prevents cell death. Finally, we observe that Pifithrin-alpha and CHX effectively inhibit PUMA expression by UV irradiation. Taken together, these data indicate that the nuclear p53 promotes PUMA expression, which then displaces cytoplasmic p53 from Bcl-x(L), allowing p53 to induce mitochondrial permeabilization, thereby triggering apoptosis.
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PMID:Regulation of Bax activation and apoptotic response to UV irradiation by p53 transcription-dependent and -independent pathways. 1865 56

Here, we investigated the specific roles of Bcl-2 family members in anoxia tolerance of malignant glioma. Flow cytometry analysis of cell death in 17 glioma cell lines revealed drastic differences in their sensitivity to oxygen withdrawal (<0.1% O(2)). Cell death correlated with mitochondrial depolarization, cytochrome C release, and translocation of green fluorescent protein (GFP)-tagged light chain 3 to autophagosomes but occurred in the absence of caspase activation or phosphatidylserine exposure. In both sensitive and tolerant glioma cell lines, anoxia caused a significant up-regulation of BH3-only genes previously implicated in mediating anoxic cell death in other cell types (BNIP3, NIX, PUMA, and Noxa). In contrast, we detected a strong correlation between anoxia resistance and high expression levels of antiapoptotic Bcl-2 family proteins Bcl-xL, Bcl-2, and Mcl-1 that function to neutralize the proapoptotic activity of BH3-only proteins. Importantly, inhibition of both Bcl-2 and Bcl-xL with the small-molecule BH3 mimetics HA14-1 and BH3I-2' and by RNA interference reactivated anoxia-induced autophagic cell death in previously resistant glioma cells. Our data suggest that endogenous BH3-only protein induction may not be able to compensate for the high expression of antiapoptotic Bcl-2 family proteins in anoxia-resistant astrocytomas. They also support the conjecture that BH3 mimetics may represent an exciting new approach for the treatment of malignant glioma.
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PMID:BH3 mimetics reactivate autophagic cell death in anoxia-resistant malignant glioma cells. 1867 Jun 45

We have previously shown that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress-induced apoptosis, and this involves activation of the mitogen-activated protein/extracellular signal-regulated kinase (MEK)/ERK signaling pathway and expression of the apoptosis repressor with caspase recruitment domain (ARC) protein in the cells. In the present study, we show that up-regulation of the antiapoptotic Bcl-2 family member Mcl-1 is another mechanism critical for protection of melanoma cells against ER stress-induced apoptosis. Inhibition of Mcl-1 by small interference RNA (siRNA) rendered melanoma cells sensitive to apoptosis induced by the ER stress inducers thapsigargin and tunicamycin, but this sensitization was partially reversed by siRNA knockdown of PUMA or Noxa, as shown in Mcl-1-deficient melanoma cells. Both PUMA and Noxa were increased by ER stress through transcriptional up-regulation, but only up-regulation of Noxa was dependent on p53, whereas up-regulation of PUMA seemed to be mediated by a p53-independent mechanism(s). Up-regulation of Mcl-1 was also due to increased transcription that involved the IRE1alpha and activating transcription factor 6 signaling pathways of the unfolded protein response. In addition, activation of the MEK/ERK signaling pathway seemed to be necessary for optimal up-regulation of Mcl-1. Taken together, these results reveal the mechanisms of resistance of melanoma cells to apoptosis induction mediated by BH3-only proteins upon ER stress, and identify Mcl-1 as a target for the treatment of melanoma in combination with therapeutics that induce ER stress.
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PMID:Up-regulation of Mcl-1 is critical for survival of human melanoma cells upon endoplasmic reticulum stress. 1870 95


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