UNIPROT:P10415 - FACTA Search

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

A vast variety of naturally occurring substances have been shown to protect against experimental carcinogenesis and an increasing amount of evidence suggests that kaempferol may have cancer chemopreventative properties. However, the precise underlying protective mechanisms are poorly understood. To elucidate these mechanisms, we challenged human lung cancer cell line A549 with kaempferol and investigated its effects upon cellular growth and signal transduction pathways. Treatment of A549 cells with kaempferol resulted in a dose- and time-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 0.9+/-0.5, 5.2+/-1.5, 16.8+/-2.0, 25.4+/-2.6, and 37.8+/-4.5% on treatment with 0, 17.5, 35.0, 52.5, and 70.0 microM kaempferol, respectively. Concomitantly, kaempferol treatments led to a 1.2-, 2.7-, 3.3-, and 3.4-fold increase in Bax. Similar elevations were also observed in Bad which increased 1.2-, 3.3-, 3.7-, and 4.7-fold, respectively, as compared to control. Bcl-2 and Bcl-xL expression were inhibited in a dose-dependent fashion. While the Akt-1 and phosphorylated Akt-1 were inhibited, the mitogen-activated protein kinase (MAPK) was activated upon kaempferol treatment. Kaempferol induced apoptosis was associated with the cleavage of caspase-7 and poly ADP-ribose polymerase (PARP). Inhibition of MEK1/2 but not PI-3 kinase blocked kaempferol-induced cleavage of caspase-7, PARP cleavage, and apoptosis. The results suggest that inactivation of Akt-1 and alteration of Bcl-2 family of proteins are not sufficient for kaempferol to induce apoptosis and activation of MEK-MAPK is a requirement for kaempferol-induced cell death machinery in A549 cells.
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PMID:Kaempferol-induced growth inhibition and apoptosis in A549 lung cancer cells is mediated by activation of MEK-MAPK. 1294 47

Aromatase inhibitors have recently been reported to be more effective than the antiestrogen tamoxifen (Tam) in treating breast cancer. Here, we studied the mechanisms and signaling pathways of cell growth, cell cycle progression, and apoptosis induced by three aromatase inhibitors: letrozole (Let), anastrozole, and 4-hydroxyandrostenedione in comparison with estrogen withdrawal (E2W) and antiestrogens Tam and faslodex. Estrogen-dependent human breast cancer cells stably transfected with aromatase (MCF-7Ca) were used. All treatments induced growth suppression and cell cycle arrest at the G(0)-G(1) phase that was associated with up-regulation of p53 and p21 protein and mRNA levels and down-regulation of cyclin D1 and c-myc mRNA. The apoptotic index was increased 4-7 fold, Bcl-2 protein expression decreased, Bax increased, and caspase-9, caspase-6, and caspase-7 were activated but not caspase-3 and caspase-8. Let and E2W caused regression of tumors of MCF-7Ca cells grown in nude mice and increased the number of cells undergoing apoptosis. In contrast, Tam and faslodex did not induce tumor regression and a lower number of apoptotic cells was detected. Cleavage of poly(ADP-ribose) polymerase was detected. Treatment with Let, Tam, or E2W resulted in a dose- and time-dependent increase in active caspase-7 and up-regulation of p53 and p21 protein. Although the mechanisms involved appeared to be similar for antiestrogens and aromatase inhibitors, the most significant effects occurred with Let, which were significantly greater than with E2W and consistent with marked effects of Let on tumor and cell growth.
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PMID:Signaling pathways of apoptosis activated by aromatase inhibitors and antiestrogens. 1463 37

Dietary phytochemicals have been shown to be protective against various types of cancers. However, the precise underlying protective mechanisms are poorly understood. In the present study, we report that treatment of A549 cells with quercetin resulted in a dose-dependent reduction in cell viability and DNA synthesis with the rate of apoptosis equivalent to 1.2 +/- 0.8, 6.3 +/- 0.9, 16.5 +/- 1.5, 36.4 +/- 2.6 and 42.5 +/- 5.8% on treatment with 0.1% dimethylsulfoxide, 14.5, 29.0, 43.5 and 58.0 micro M quercetin, respectively. Concomitantly, quercetin treatments led to a 1.1-, 1.1-, 2.5- and 3.5-fold increase in Bax. Similar elevations were also observed in Bad, which increased 1.1-, 2.1-, 2.2- and 2.3-fold, respectively, as compared with control. While Bcl-2 was decreased by 30%, Bcl-x(L) was elevated in a dose-dependent fashion. Quercetin also induced the cleavage of caspase-3, caspase-7 and PARP (poly ADP-ribose polymerase). While Akt-1 and phosphorylated Akt-1 were inhibited, the extracellular signal-regulated kinase (ERK) was phosphorylated following quercetin treatment in a dose-dependent fashion. Phosphorylation of ERK and c-Jun occurred at 3 h and was sustained over 14 h. Phosphorylation of MEK1/2 was increased in concordance with ERK activation. Quercetin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and cleavage of caspase-3 occurred 6 h after quercetin exposure and before cleavage of caspase-7 and PARP was detected. Inhibition of MEK1/2 but not PI-3 kinase, p38 kinase or JNK abolished quercetin-induced phosphorylation of c-Jun, cleavage of caspase-3 and -7, cleavage of PARP and apoptosis. Inhibition of caspase activation completely blocked quercetin-induced apoptosis. Expression of constitutively activated MEK1 in A549 cells led to activation of caspase-3 and apoptosis. The results suggest that in addition to inactivation of Akt-1 and alteration in the expression of the Bcl-2 family of proteins, activation of MEK-ERK is required for quercetin-induced apoptosis in A549 lung carcinoma cells.
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PMID:The role of activated MEK-ERK pathway in quercetin-induced growth inhibition and apoptosis in A549 lung cancer cells. 1468 22

Interferon (IFN)-alpha directly inhibits proliferation of liver cancer cells by inducing apoptosis, but the molecular mechanisms by which IFN-alpha induces apoptosis in these cells are not fully understood. We examined the effect of broad spectrum caspase inhibitor, Z-VAD-fmk, and the caspase activation in IFN-alpha-mediated apoptosis by using 4 liver cancer cell lines that were sensitive or resistant to IFN-alpha-mediated apoptosis. Involvement of apoptosis-related mitochondrial proteins and Bcl-2 family proteins in IFN-alpha-mediated apoptosis was further examined in 1 sensitive cell line (KIM-1). The Z-VAD-fmk completely or moderately inhibited IFN-alpha-mediated apoptosis in the sensitive cells. IFN-alpha induced time-dependent activation of caspase-3 in the sensitive cells, while the resistant cells showed mild or no activation. Activation of caspase-9, caspase-8, and caspase-7, and the cleavage of poly(ADP-ribose)polymerase were identified in either or both of the sensitive cell lines, but not in the resistant cells. In KIM-1 cells, the release of cytochrome c and Smac/DIABLO from mitochondria to cytosole was confirmed. Meanwhile, Bcl-xL was upregulated, and Bid activation or translocation, or conformational changes of Bax were not identified. In conclusion, our results suggest IFN-alpha-mediated apoptosis in liver cancer cells involves the mitochondrial apoptotic pathway and is induced by activating various caspases.
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PMID:Expression and activation of apoptosis-related molecules involved in interferon-alpha-mediated apoptosis in human liver cancer cells. 1587 Aug 81

Postmenopausal women with estrogen receptor positive (ER(+)) breast cancer frequently respond paradoxically to estrogen administration with tumor regression. Using both LTED and E8CASS cells derived from MCF-7 breast cancer cells by long-term estrogen-deprivation, we previously reported that 17beta -estradiol (estradiol) is a powerful, pro-apoptotic hormone which kills the cancer cells through activation of the Fas/FasL death receptor pathway. We postulated that the mitochondrial interactive protein Bcl-2 might play a role in the regulation of estradiol-induced apoptosis in both LTED and E8CASS cells. In this study, we assessed estradiol effects on cell growth, proliferation and apoptosis. Additionally we investigated the effect of estradiol on caspase activation, NF-KB and Bcl-2 expression. The functional role of Bcl-2 in estradiol-induced apoptosis was further studied by knockdown or decrease of Bcl-2 with siRNA. Our results show that estradiol significantly inhibited cell growth primarily through a pro-apoptotic action involving caspase-7 and 9 activations (p < 0.01). Basal Bcl-2 and NF-KB levels were greatly elevated and estradiol decreased NF-KB, but not Bcl-2 expression. Knockdown of Bcl-2 expression with siRNA decreased the levels of this protein by 9 fold (p < 0.01). This reduction markedly sensitized both LTED and E8CASS cells to the pro-apoptotic action of estradiol, leading to a synergistic induction of apoptosis and a concomitant reduction in cell number (p < 0.01). Therefore, down-regulation of Bcl-2 synergistically enhanced estradiol-induced apoptosis in ER(+) postmenopausal breast cancer cells.
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PMID:Down-regulation of Bcl-2 enhances estrogen apoptotic action in long-term estradiol-depleted ER(+) breast cancer cells. 1590 28

The fragile histidine triad (FHIT) gene is a frequent target of deletions in lung cancer. Previous studies have shown that FHIT gene transfer into lung cancer cells lacking FHIT expression results in induction of apoptosis. However, the effect of FHIT expression on apoptosis induced by chemotherapeutic agents and its intracellular mechanism is poorly understood. This study was undertaken to elucidate the effect of FHIT expression and the role of Bcl-2-caspase signaling in paclitaxel-induced apoptosis in lung cancer cells. NCI-H358 lung cancer cells, which lack FHIT expression, were stably transfected with plasmid vector containing FLAG-tagged wildtype FHIT. We investigated effects of paclitaxel on apoptosis, activation of caspase system and expression of Bcl-2 family. We next evaluated whether these effects were reversed by blocking FHIT expression using siRNA. Paclitaxel enhanced apoptosis in FHIT-expressing cells compared to that in control vector-transfected cells, and this enhancement was suppressed by siRNA treatment. Activities of caspase-3 and caspase-7, but not of caspase-8, were higher in FHIT-expressing cells than in control vector-transfected cells, and this was reduced by siRNA treatment. When caspase activation was blocked by a pan-caspase inhibitor in FHIT-expressing cells, paclitaxel-induced apoptotic cell death was decreased similar to that in control vector-transfected cells. Bcl-2 and Bcl-xL expressions were down-regulated after paclitaxel treatment in FHIT-expressing cells, whereas Bax and Bad expressions were up-regulated. These were reversed by siRNA treatment. These results indicate that paclitaxel-induced apoptosis enhanced by FHIT expression in lung cancer cells might be associated with modulation of Bcl-2-caspase signaling.
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PMID:FHIT protein enhances paclitaxel-induced apoptosis in lung cancer cells. 1623 22

Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent PC3 prostate cancer cells. An antisense oligonucleotide with complete sequence identity to Bcl-2 and three-base mismatches to Bcl-xL selected from five antisense oligonucleotides targeting various regions with high homology between Bcl-2 and Bcl-xL was found to be the most potent inhibitor of both Bcl-2 and Bcl-xL expression in PC3 cells. This selected Bcl-2/Bcl-xL bispecific antisense oligonucleotide reduced mRNA and protein levels in a dose-dependent manner, reducing Bcl-2 and Bcl-xL protein levels to 12% and 19%, respectively. Interestingly, Mcl-1 was down-regulated as well, although levels of Bax, Bad, or Bak were not altered after treatment with this bispecific antisense oligonucleotide. Indirect down-regulation of inhibitor of apoptosis (IAP) family, including XIAP, cIAP-1 and cIAP-2, via second mitochondria-derived activator of caspases was also observed after bispecific antisense oligonucleotide treatment. Executioner caspase-3, caspase-6, and caspase-7 were shown to be involved in apoptosis induced by bispecific antisense oligonucleotide. This Bcl-2/Bcl-xL bispecific antisense oligonucleotide also enhanced paclitaxel chemosensitivity in PC3 cells, reducing the IC50 of paclitaxel by >90%. These findings illustrate that combined suppression of antiapoptotic Bcl-2 family members using this antisense oligonucleotide could be an attractive strategy for inhibiting cancer progression through alteration of the apoptotic rheostat in androgen-independent prostate cancer.
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PMID:A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells. 1627 90

SIRT1 is a conserved NAD-dependent deacetylase that regulates life span in accord with nutritional provision. In mammalian cells, SIRT1 also down-regulates stress-induced p53 and FoxO pathways for apoptosis, thus favoring survival under stress. The functioning of SIRT1 under normal, nonstressed conditions of cell growth is unknown. Here we have asked if SIRT1 has the capacity to influence cell viability in the absence of applied stress. For this purpose we used synthetic small interfering RNA to silence SIRT1 gene expression by RNA interference (RNAi). We show that the process of RNAi, by itself, does not affect cell growth and is not sufficient to activate a cellular stress response (indicated by lack of activation of endogenous p53). We also show that, in the absence of applied stress, SIRT1 silencing induces growth arrest and/or apoptosis in human epithelial cancer cells. In contrast, normal human epithelial cells and normal human diploid fibroblasts seem to be refractory to SIRT1 silencing. Combined gene knockout with RNAi cosilencing experiments indicate that SIRT1 and Bcl-2 may suppress separable apoptotic pathways in the same cell lineage and that the SIRT1-regulated pathway is independent of p53, Bax, and caspase-2. Alternatively, SIRT1 may suppress apoptosis downstream from these apoptotic factors. In either case, we show that FoxO4 (but not FoxO3) is required as proapoptotic mediator. We further identify caspase-3 and caspase-7 as downstream executioners of SIRT1/FoxO4-regulated apoptosis. Our work identifies SIRT1 as a novel target for selective killing of cancer versus noncancer epithelial cells.
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PMID:Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival. 1628 37

To decipher the pathway of apoptosis induction downstream to caspase-8 activation by exogenous expression of Hippi, an interactor of huntingtin-interacting protein Hip1, we studied apoptosis in HeLa and Neuro2A cells expressing GFP-tagged Hippi. Nuclear fragmentation, caspase-1, caspase-8, caspase-9/caspase-6 and caspase-3 activation were increased significantly in Hippi expressing cells. Cleavage of Bid, release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria were also increased in GFP-Hippi expressing cells. It was observed that caspase-1 and caspase-8 activation was earlier than caspase-3 activation and nuclear fragmentation. Expression of caspase-1, caspase-3 and caspase-7 was increased while anti-apoptotic gene Bcl-2 and mitochondrial genes ND1 and ND4 were reduced in Hippi expressing cells. Besides, the expression SDHA and SDHB, nuclear genes, subunits of mitochondrial complex II were decreased in GFP-Hippi expressing cells. Taken together, we concluded that Hippi expression induced apoptosis by releasing AIF and cytochrome c from mitochondria, activation of caspase-1 and caspase-3, and altering the expression of apoptotic genes and genes involved in mitochondrial complex I and II.
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PMID:Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1. 1636 50

The present study investigates the relationship between the subcellular localisation of Foscan and intrinsic apoptotic pathway post Foscan-based photodynamic therapy (PDT). With this purpose, mammary carcinoma MCF-7 cells were incubated with Foscan for 3 or 24 h and then subjected to equitoxic light doses. Fluorescence microscopy revealed very good Foscan co-localization to endoplasmic reticulum (ER) and Golgi apparatus after 3 h incubation with MCF-7 cells. Progressive increase in incubation time shows leakage of Foscan from Golgi apparatus. Twenty-four hours incubation yielded a fluence-dependent enhanced induction of the ER-resident glucose-regulated protein 78 (Bip/GRP78), along with a weak mitochondrial damage, thus underscoring the ER as the main site of photodamage after prolonged incubation. Analysis of events implicated in apoptotic pathway after 24 h incubation demonstrated photodamage to Bcl-2 protein in total cellular extract, but not in the mitochondrial fraction. We further determined an increase in caspases-7 and -6 activation, which was strongly related to the expression of GRP78. The above findings demonstrate that Foscan localisation in ER improves the photoactivation of the caspase-7 apoptotic pathway, which is poorly related to mitochondrial damage.
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PMID:Relationship between subcellular localisation of Foscan and caspase activation in photosensitised MCF-7 cells. 1732 8

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