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)

Using adenoviral technology, we overexpressed the proapoptotic molecules pro-caspase-3, pro-caspase-7, and Bax to induce therapeutic apoptosis of prostate cancer cell lines growing in vitro and in vivo. Because overexpressed pro-caspase-3 did not undergo autocatalytic activation in any of the five prostate cancer cell lines evaluated, this strategy was unable to engage any component of the apoptotic pathway. Overexpressed pro-caspase-7 was proteolytically cleaved in LNCaP and LnCaP-Bcl-2 cells but not in PC-3, DU-145, or TsuPr(1) cells. Cleavage was associated with engagement of many components of the apoptotic pathway, including DEVDase activity, cleavage of intracellular caspase targets such as the DNA fragmentation factor and the proapoptotic Bid, release of cytochrome c from the mitochondria to the cytoplasm, and terminal deoxynucleotidyl transferase-mediated nick end labeling. No apoptosis was observed in the cells where caspase-7 did not undergo autocatalytic activation. Searching for an approach that would more reliably induce therapeutic apoptosis of prostate cancer cell lines, we used a binary adenoviral system to overexpress the proapoptotic molecule Bax. Bax was dramatically overexpressed and caused apoptosis of every cell line infected by engaging the mitochondrial pathway, including proteolytic cleavage and catalytic activation of the caspases, cleavage of caspase substrates, release of cytochrome c from the mitochondria, and DNA fragmentation. Furthermore, three injections of the Bax overexpression system into PC-3 cell tumors in nude mice in vivo caused a 25% regression in tumor size corresponding to a 90% reduction relative to continued tumor growth in animals that received injections with the control binary system expressing Lac-Z. These experiments show that adenovirus-mediated Bax overexpression is capable of inducing therapeutic programmed cell death in vitro and in vivo by activating the mitochondrial pathway of apoptosis. On the basis of these studies, we conclude that manipulation of Bax expression is an attractive new gene therapy approach for the treatment of prostate cancer.
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PMID:Adenovirus-mediated Bax overexpression for the induction of therapeutic apoptosis in prostate cancer. 1119 58

Apoptotic proteases cleave and inactivate survival signaling molecules such as Akt/PKB, phospholipase C (PLC)-gamma1, and Bcl-2. We have found that treatment of A431 cells with tumor necrosis factor-alpha in the presence of cycloheximide resulted in the cleavage of epidermal growth factor receptor (EGFR) as well as the activation of caspase-3. Among various caspases, caspase-1, caspase-3 and caspase-7 were most potent in the cleavage of EGFR in vitro. Proteolytic cleavage of EGFR was inhibited by both YVAD-cmk and DEVD-fmk in vitro. We also investigated the effect of caspase-dependent cleavage of EGFR upon the mediation of signals to downstream signaling molecules such as PLC-gamma1. Cleavage of EGFR by caspase-3 significantly impaired the tyrosine phosphorylation of PLC-gamma1 in vitro. Given these results, we suggest that apoptotic protease specifically cleaves and inactivates EGFR, which plays crucial roles in anti-apoptotic signaling, to abrogate the activation of EGFR-dependent downstream survival signaling molecules.
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PMID:Proteolytic cleavage of epidermal growth factor receptor by caspases. 1122 7

Heregulins are a group of growth factors that play diverse and critical roles in the signaling network of the human epidermal growth factor receptor (HER or EGFR) superfamily. Our earlier studies have shown that recombinant heregulinbeta1 (HRG) induces apoptosis in SKBr3 breast cancer cells that overexpress HER2. Here we report molecular mechanisms of HRG-induced apoptosis. HRG treatment of SKBr3 cells for 72 h decreased the level of Bcl-2 protein. HRG treatment led to degradation of poly (ADP-ribose) polymerase (PARP) and activated both caspase-9 and caspase-7. No significant activation of caspase-3, -6, or -8 was detected. Expression of exogenous caspase-7 by adenovirus-caspase-7 (Ad-casp-7) in SKBr3 cells resulted in apoptosis, which mimicked the effect of HRG treatment. Expression of exogenous caspase-7 had no impact on Bcl-2 expression, but promoted PARP degradation. Two highly selective inhibitors of protein kinase C (PKC), GF109203X (GF) and Ro318425 (Ro), significantly enhanced HRG-induced apoptosis as determined by flow cytometric analysis and DNA fragmentation assay. Accordingly, the PKC inhibitor GF further decreased the level of Bcl-2 protein and further degraded PARP in HRG-treated cells. Assay of PKC activity indicated that HRG activated PKC in SKBr3 cells, predominantly affecting the PKCalpha isoform. To confirm which PKC isoform(s) mediated potentiation of HRG-induced apoptosis, the profile of PKC isoforms was measured in SKBr3 cells. Five PKC isoforms, PKCalpha, PKCiota, PKCzeta, PKClambda, and PKCdelta as well as their receptors (RACK1) were expressed in this cell line. Treatment with PKC inhibitors GF and Ro decreased protein levels of both PKCalpha and PKCdelta at 24 h. PKCalpha levels were still depressed at 72 h. GF and Ro had little effect on the expression of other PKC isoforms. An inhibitor of classical PKC isoforms (Go6976) enhanced HRG-induced apoptosis, whereas the PKCdelta selective inhibitor rottlerin did not. As PKCalpha was the only classical isoform expressed in SKBr3 cells, the effect of Go6976 on HRG-induced apoptosis largely related to inhibition of PKCalpha. Constitutive expression of wild-type PKCalpha attenuated the apoptosis produced by HRG and GF. Consequently, HRG-induced apoptosis in SKBr3 cells appeared to involve down-regulation of Bcl-2 protein, activation of caspase-9 and caspase-7, and degradation of PARP. Inhibition of PKC function enhanced HRG-induced apoptosis, leading to synergistic down-regulation of Bcl-2 expression. Impairment of the PKCalpha isoform alone was sufficient to potentiate HRG-induced apoptosis.
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PMID:Heregulin-induced apoptosis is mediated by down-regulation of Bcl-2 and activation of caspase-7 and is potentiated by impairment of protein kinase C alpha activity. 1178 40

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is one of the latest members of the TNF superfamily known to induce apoptosis in a wide variety of tumor cells. Some cell types, however, are quite resistant to TRAIL. We investigated the effect of ectopic expression of Bcl-2 and Bcl-xL on TRAIL-induced apoptosis in human acute myelogenous leukemia HL-60 cells. We found that HL-60 cells, which express TRAIL receptors (also called death receptor, DR) DR4, DR5, and Dc (decoy) R2, are highly sensitive to TRAIL-induced cytotoxicity. Greater than 90% killing occurred within 24 h of TRAIL treatment. The expression of Bcl-2 and Bcl-xL, however, completely abolished the TRAIL-induced cytotoxic effects. Treatment of HL-60 cells with TRAIL induced caspase-8 activation within 2-4 h, but no activation could be seen in Bcl-2-expressing or Bcl-xL-expressing cells. TRAIL also induced cleavage of BID, which was also abolished by Bcl-2 and Bcl-xL. Similarly, TRAIL activated caspase-3 and caspase-7 in control cells but not in cells expressing Bcl-2 or Bcl-xL. Cleavage of the caspase-3 substrate poly(ADP-ribose) polymerase (PARP), was abrogated by ectopic expression of Bcl-2 and Bcl-xL. Inhibition of caspases by the pan-caspase inhibitor, benzyloxycarbonyl-valine-alanine-aspartate-fluoromethylketone (zVAD-fmk) abolished the TRAIL-induced apoptosis. Overall, these results indicate that TRAIL-induced apoptosis involves activation of caspase-8, caspase-7, caspase-3, and BID cleavage, and Bcl-2 and Bcl-xL prevents TRAIL-induced apoptosis by abrogating caspase activation and BID cleavage.
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PMID:Ectopic expression of Bcl-2 and Bcl-xL inhibits apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL) through suppression of caspases-8, 7, and 3 and BID cleavage in human acute myelogenous leukemia cell line HL-60. 1191 10

Engagement of the B cell Ag receptor (BCR) on immature B cells leads to growth arrest followed by apoptosis. Concomitant signaling through CD40 sustains proliferation and rescues the cells from apoptosis. Previously, we have shown that cross-linking CD40 on B cells stimulates the expression of A1, an antiapoptotic member of the Bcl-2 family, and that transduction of the murine B lymphoma line WEHI 231, a model for immature B cells, with A1 protected the cells against BCR-induced apoptosis. Here we demonstrate that A1 strongly interferes with activation of caspase-7, the major effector caspase activated after BCR cross-linking on WEHI 231 lymphoma cells. The pathway leading to activation of the effector caspase cascade including caspase-7 is unclear. Using retrovirally transduced WEHI 231 cell populations, we show that a catalytically inactive mutant of caspase-7 is cleaved almost as efficiently as the wild-type form, arguing against autocatalysis as the sole activating process. In contrast, overexpression of catalytically inactive caspase-9 strongly interferes with caspase-7 processing, poly(ADP-ribose) polymerase cleavage, and DNA laddering, suggesting a role for caspase-9 and hence for the mitochondrial pathway. The importance of the mitochondrial/caspase-9 pathway for BCR-triggered apoptosis is highlighted by our finding that both A1 and the mutant caspase-9 attenuate BCR-induced apoptosis. Thus, our data suggest that the BCR-mediated apoptotic signal in immature B cells spreads via a mitochondrial/caspase-9 pathway.
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PMID:Mitochondria-dependent caspase-9 activation is necessary for antigen receptor-mediated effector caspase activation and apoptosis in WEHI 231 lymphoma cells. 1193 45

Extensive studies have implicated the role of dietary fatty acids in prostatecancer progression. Platelet-type 12-Lipoxygenase (12-LOX) has beenshown to regulate growth, metastasis, and angiogenesis of prostate cancer. The effect of two 12-LOX inhibitors, Baicalein and N-benzyl-N-hydroxy-5-phenylpentamide (BHPP), on the mechanisms controlling cell cycle progression and apoptosis were examined in two prostate cancer cell lines, PC3 and DU-145. Treatment with Baicalein or BHPP resulted in a dose-dependent decrease in cell proliferation, as measured by BrdUrd incorporation. This growth arrest was shown to be because of cell cycle inhibition at G0/G1, and was associated with suppression of cyclin D1 and D3 protein levels. PC3 cells also showed a strong decrease in phosphorylated retinoblastoma (pRB) protein, whereas the other retinoblastoma-associated proteins, p107 and p130, were inhibited in DU-145 cells. Treatment with 12-hydroxyeicosatetraenoic acid in the presence of Baicalein blocked loss of pRB, whereas 12(S)-HETE alone induced pRB expression. Treatment with either Baicalein or BHPP resulted in significant apoptosis in both cell lines as measured by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. DU-145 cells underwent apoptosis more rapidly than PC-3 cells. The mechanisms involved were decreased phosphorylation of Akt, loss of survivin and subsequent activation of caspase-3 and caspase-7 in each cell line, decreased Bcl-2 and Bcl-X(L) expression in DU-145, and a shift in Bcl-2/Bax levels favoring apoptosis in PC-3 cells. Addition of 12(S)-HETE protected both cell lines from Baicalein-induced apoptosis, whereas other LOX metabolites, 5(S)-HETE, or 15(S)-HETE did not. These results show that the 12-LOX pathway is a critical regulator of prostate cancer progression and apoptosis, by affecting various proteins regulating these processes. Therefore, inhibition of 12-LOX is a potential therapeutic agent in the treatment of prostate cancer.
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PMID:Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells. 1198 Jun 74

Previous experimental studies have shown that high dietary fat intake is associated with mammary carcinogenesis. In the current study, the effect of 5-LOX or 12-LOX inhibitors on human breast cancer cell proliferation and apoptosis, as well as the possible mechanisms were investigated. The LOX inhibitors, NDGA, Rev-5901, and baicalein all inhibited proliferation and induced apoptosis in MCF-7 (ER+) and MDA-MB-231 (ER-) breast cancer cell in vitro. In contrast, the LOX products, 5-HETE and 12-HETE had mitogenic effects, stimulating the proliferation of both cell lines. These inhibitors also induced cytochrome c release, caspase-9 activation, as well as downstream caspase-3, caspase-7 activation, and PARP cleavage. LOX inhibitor treatment also reduced the levels of anti-apoptotic proteins Bcl-2 and Mcl-1 and increased the levels of the pro-apoptotic protein bax. In conclusion, blockade of both 5-LOX and 12-LOX pathways induces apoptosis in breast cancer cells through the cytochrome c release and caspase-9 activation, with changes in the levels of Bcl-2 family proteins.
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PMID:The mechanisms of lipoxygenase inhibitor-induced apoptosis in human breast cancer cells. 1220 Jan 39

Because of the central role of the transcription factor nuclear factor-kappaB (NF-kappaB) in cell survival and proliferation in human multiple myeloma (MM), we explored the possibility of using it as a target for MM treatment by using curcumin (diferuloylmethane), an agent known to have very little or no toxicity in humans. We found that NF-kappaB was constitutively active in all human MM cell lines examined and that curcumin, a chemopreventive agent, down-regulated NF-kappaB in all cell lines as indicated by electrophoretic mobility gel shift assay and prevented the nuclear retention of p65 as shown by immunocytochemistry. All MM cell lines showed consitutively active IkappaB kinase (IKK) and IkappaBalpha phosphorylation. Curcumin suppressed the constitutive IkappaBalpha phosphorylation through the inhibition of IKK activity. Curcumin also down-regulated the expression of NF-kappaB-regulated gene products, including IkappaBalpha, Bcl-2, Bcl-x(L), cyclin D1, and interleukin-6. This led to the suppression of proliferation and arrest of cells at the G(1)/S phase of the cell cycle. Suppression of NF-kappaB complex by IKKgamma/NF-kappaB essential modulator-binding domain peptide also suppressed the proliferation of MM cells. Curcumin also activated caspase-7 and caspase-9 and induced polyadenosine-5'-diphosphate-ribose polymerase (PARP) cleavage. Curcumin-induced down-regulation of NF-kappaB, a factor that has been implicated in chemoresistance, also induced chemosensitivity to vincristine and melphalan. Overall, our results indicate that curcumin down-regulates NF-kappaB in human MM cells, leading to the suppression of proliferation and induction of apoptosis, thus providing the molecular basis for the treatment of MM patients with this pharmacologically safe agent.
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PMID:Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. 1239 61

Association between the rate of apoptosis and expression of the several relevant molecules (Bcl-2, pro- and active caspase-3, and caspase-7) was studied in 61 primary breast carcinomas. The rate of apoptosis detected both morphologically and by the TUNEL assay appeared to be high in 18 (30%), moderate in 14 (23%), and low in 29 (48%) carcinomas. High apoptotic index was strongly associated with advanced tumor grade and estrogen receptor positive (ER+) status but not with other investigated clinical or morphological parameters. Among the molecules studied, only the Bcl-2 protein expression demonstrated strong (inverse) correlation with the apoptotic index (p = 0.032). The data of this expected correlation was served as internal control in the study. Interestingly, high levels of the anti-apoptotic protein Bcl-2 was frequently co-incident with increased expression of pro-apoptotic molecules, such as active caspase-3 (p = 0.004) and caspase-7 (p = 0.001). However, expression of caspase-3 or caspase-7 did not show correlation with the extent of apoptosis or any clinico-morphological features, except overrepresentation of ER+ status in tumors expressing caspase-3 (p = 0.009). Thus, these findings indicate a general dysregulation of spontaneous apoptosis in primary breast tumors.
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PMID:Expression of caspase-3 and -7 does not correlate with the extent of apoptosis in primary breast carcinomas. 1246 Dec 96

Several studies have suggested that high dietary fat intake, particularly essential fatty acids, is associated with pancreatic cancer development and growth. Our previous studies have demonstrated that blockade of either the 5-lipoxygenase (LOX) or 12-LOX pathway of arachidonic acid metabolism inhibited pancreatic cancer cell proliferation and induced apoptosis. This study investigated the underlying mechanisms for LOX inhibitor-induced apoptosis and the potential of LOX inhibitors as antipancreatic cancer agents using the athymic mice xenograft model. Apoptosis of pancreatic cancer cells induced by LOX inhibitors (including the nonselective LOX inhibitor nordihydroguaiaretic acid, the 5-LOX inhibitor Rev-5901, and the 12-LOX inhibitor baicalein) was confirmed by growth inhibition, annexin V binding, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay in MiaPaCa-2 and AsPC-1 human pancreatic cancer cells. Expression of the antiapoptotic proteins Bcl-2 and Mcl-1 was significantly decreased after LOX inhibitor treatment while that of the proapoptotic protein bax was increased. LOX inhibitors also markedly induced the release of cytochrome c from mitochondria into the cytosol. Caspase-9, caspase-7, and caspase-3 but not caspase-8 were activated after treatment, concomitant with cleavage of the capase-3 substrate poly(ADP-ribose) polymerase. In vivo studies in the athymic mice xenograft model also confirmed the growth inhibitory effect and induction of apoptosis by these LOX inhibitors in pancreatic cancer. In conclusion, LOX inhibitors block pancreatic cancer cell proliferation and induce apoptosis through the mitochondrial pathway both in vivo and in vitro. LOX inhibitors are likely to be valuable for the treatment of human pancreatic cancer.
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PMID:Lipoxygenase inhibitors attenuate growth of human pancreatic cancer xenografts and induce apoptosis through the mitochondrial pathway. 1248 14

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