Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.62 (caspase-9)
 7,507 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the molecular mechanisms involved in the anti-proliferative activity exerted by conjugated linoleic acid (CLA) on the estrogen unresponsive MDA-MB-231 human breast cancer cell line. The effects on cell proliferation, cell cycle progression and induction of apoptosis were examined. CLA caused the reduction of cell proliferation along with the accumulation of cells in the S phase of the cycle. The occurrence of apoptosis in these cells was indicated by flow cytometry data and further confirmed by the onset of cells with morphological features typical of apoptosis. ERK1/2 reduction and upregulation of pro-apoptotic protein Bak were induced. These events were associated with: (a) reduced levels of the anti-apoptotic protein Bcl-x(L), (b) the translocation of cytochrome c from the mitochondria to the cytosol, (c) the cleavage of pro-caspase-9 and pro-caspase-3. From the above data, we are induced to think that CLA may trigger apoptosis in the estrogen unresponsive MDA-MB-231 cell line via mechanisms involving above all the mitochondrial pathway.
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PMID:Conjugated linoleic acid induces apoptosis in MDA-MB-231 breast cancer cells through ERK/MAPK signalling and mitochondrial pathway. 1588 90

The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression of HIF-1alpha has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1alpha-induced survival pathways in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1alpha suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Overexpression of HIF-1alpha inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca(2+) concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, antiapoptotic Bcl-2 and Bcl-X(L) levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1alpha-overexpressing OSCC line. Overexpression of HIF-1alpha also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1alpha prevents apoptotic cell death through two mechanisms, including inhibition of cytochrome c release and activation of Akt and ERK.
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PMID:Mechanism of HIF-1alpha-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells. 1605 10

Many isothiocysanates (ITC) are promising cancer-preventive agents, and induction of apoptosis is one of their underlying mechanisms of action. We recently found that caspase-9 was preferentially activated over other initiator caspases in human bladder cancer UM-UC-3 cells. We report here that caspase-9 activation is the major step leading to ITC-induced apoptosis in this cell line. More importantly, our results show that caspase-9 activation by the ITCs may result primarily from mitochondrial damage. Four common naturally occurring ITCs were studied, including allyl ITC, benzyl ITC (BITC), phenethyl ITC (PEITC), and sulforaphane. BITC and PEITC showed more potent mitochondria-damaging ability than the other two ITCs, correlating well with their stronger apoptosis-inducing potentials. Furthermore, BITC and PEITC damaged both the outer and inner mitochondrial membranes. Use of isolated mitochondria allowed us to establish that ITCs, and more importantly their major intracellular derivatives (glutathione conjugates) at concentrations that are readily achievable in cells, damage mitochondria, leading to the collapse of mitochondrial trans-membrane potential and release of cytochrome c. The mitochondria-damaging potencies of the ITCs correlate well with their lipophilicities. Bcl-2 family members are known to influence the stability of mitochondrial membrane. Our results show that the ITCs caused phosphorylation of Bcl-2, induced mitochondrial translocation of Bak, and disrupted the association of Bcl-xl with both Bak and Bax in mitochondrial membrane, indicating that ITC-induced mitochondrial damage results at least in part from modulation of select Bcl-2 family members.
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PMID:Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells. 1609 41

In the present study, we aimed to elucidate the mechanism responsible for the interactive effects of histone deacetylase (HDAC) inhibitors [suberoylanilide hydroxamic acid (SAHA), MS-275, m-carboxycinnamic acid bishydroxamide (CBHA), and trichostatin-A (TSA)] and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) on apoptosis in leukemia cells. HDAC inhibitors enhance the apoptosis-inducing potential of TRAIL in leukemia cells (HL60, Jurkat, K562, and U937) through multiple mechanisms; up-regulation of DR4, DR5, Bak, Bax, Bim, Noxa and PUMA, down-regulation of IAPs, Mcl-1, Bcl-2, Bcl-XL and cFLIP, release of mitochondrial proteins (cytochrome c, Smac/DIABLO and Omi/Htr2) to the cytosol, induction of p21WAF1/CIP1 and p27KIP1, activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP). The sequential treatment of cells with HDAC inhibitors followed by TRAIL was more effective in inducing apoptosis than the concurrent treatment or single agent alone. The up-regulation of death receptors and inhibition of cFLIP by HDAC inhibitors will increase the ability of TRAIL to induce apoptosis, due to enhance activation of caspase-8, cleavage of Bid, and release of mitochondrial proteins to the cytosol, and subsequent activation of caspase-9 and caspase-3. Thus, the combination of HDAC inhibitors and TRAIL can be used as a new therapeutic approach for the treatment of leukemia.
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PMID:Interactive effects of histone deacetylase inhibitors and TRAIL on apoptosis in human leukemia cells: involvement of both death receptor and mitochondrial pathways. 1627 96

The present study was undertaken to gain insights into the molecular mechanism of cell death (apoptosis) by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, using PC-3 human prostate cancer cells as a model. The viability of PC-3 cells, but not a normal prostate epithelial cell line (PrEC), was reduced significantly on treatment with guggulsterone in a concentration-dependent manner. Guggulsterone-mediated suppression of PC-3 cell proliferation was not due to perturbation in cell cycle progression but caused by apoptosis induction characterized by appearance of subdiploid cells and cytoplasmic histone-associated DNA fragmentation. Guggulsterone-induced apoptosis was associated with induction of multidomain proapoptotic Bcl-2 family members Bax and Bak. Interestingly, the expression of antiapoptotic proteins Bcl-2 and Bcl-xL was initially increased in guggulsterone-treated PC-3 cells but declined markedly following a 16- to 24-hour treatment with guggulsterone. Ectopic expression of Bcl-2 in PC-3 cells failed to confer significant protection against guggulsterone-induced cell death. On the other hand, SV40 immortalized mouse embryonic fibroblasts derived from Bax-Bak double knockout mice were significantly more resistant to guggulsterone-induced cell killing compared with wild-type cells. Guggulsterone treatment resulted in cleavage (activation) of caspase-9, caspase-8, and caspase-3, and guggulsterone-induced cell death was significantly attenuated in the presence of general caspase inhibitor as well as specific inhibitors of caspase-9 and caspase-8. In conclusion, the present study indicates that caspase-dependent apoptosis by guggulsterone is mediated in part by Bax and Bak.
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PMID:Caspase-dependent apoptosis induction by guggulsterone, a constituent of Ayurvedic medicinal plant Commiphora mukul, in PC-3 human prostate cancer cells is mediated by Bax and Bak. 1627 96

Chalcones are discussed to represent cancer preventive food components in a human diet that is rich in fruits and vegetables. In this study, we examined chalcone (1,3-diphenyl-2-propenone) for its effect on proliferation in human breast cancer cell lines, MCF-7 and MDA-MB-231. The results showed that chalcone inhibited the proliferation of MCF-7 and MDA-MB-231 by inducing apoptosis and blocking cell cycle progression in the G2/M phase. Immunoblot assay showed that chalcone significantly decreased the expression of cyclin B1, cyclin A and Cdc2 protein, as well as increased the expression of p21 and p27 in a p53-independent manner, contributing to cell cycle arrest. An enhancement in Fas/APO-1 and its two form ligands, membrane-bound Fas ligand (mFasL) and soluble Fas ligand (sFasL), was responsible for the apoptotic effect induced by chalcone. In addition, chalcone also triggered the mitochondrial apoptotic signaling by increasing the amount of Bax and Bak and reducing the level of Bcl-2 and Bcl-X(L), and subsequently activated caspase-9 in MCF-7 and MDA-MB-231 cells. Taken together, our study suggests that the blockade of cell cycle progression and initiation of cell apoptotic system may participate in the antiproliferative activity of chalcone in human breast cancer cells.
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PMID:Chalcone inhibits the proliferation of human breast cancer cell by blocking cell cycle progression and inducing apoptosis. 1630 39

Caspases play important roles in the initiation and progression of apoptosis. In experimental models of ATP depletion, we have demonstrated the activation of caspase-9, -8, and -3, which is followed by the development of apoptotic morphology. To determine the specific contribution of caspase-9 to ATP depletion-induced apoptosis, we transfected renal epithelial cells with its endogenous dominant-negative inhibitor caspase-9S. Two cell clones with stable transfection were obtained. These clones expressed caspase-9S, and the cytosol isolated from these cells was resistant to cytochrome c-induced caspase activation in vitro. The clones were then examined for ATP depletion-induced apoptosis. Compared with the wild-type cells, the caspase-9S clones were markedly resistant to apoptosis in this model. Caspase activation was also inhibited. Surprisingly, these clones also showed significantly less cytochrome c release during ATP-depletion. Moreover, Bax translocation to mitochondria was inhibited, suggesting that these clones were resistant to apoptosis not only at the cytosolic caspase activation level but also at the upstream mitochondrial level. To gain insights into the mitochondrial resistance, we analyzed the expression of Bcl-2 family proteins. While the expression of Bax, Bak, and Bcl-2 was comparable to the wild-type cells, the selected clones showed specific up-regulation of Bcl-XL, an anti-apoptotic protein. We conclude that the selected clones were resistant to apoptosis at two levels. In the cytosol, they expressed dominant negative caspase-9, and at the mitochondria they up-regulated Bcl-XL.
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PMID:Characterization of cell clones stably transfected with short form caspase-9: apoptotic resistance and Bcl-XL expression. 1631 6

Resistance of cancer cells to anoikis, apoptosis induced by cell detachment from the extracellular matrix, is thought to represent a critical feature of the malignant phenotype. Mechanisms that control anoikis of normal and cancer cells are understood only in part. Previously we found that anoikis of non-malignant intestinal epithelial cells is driven by detachment-induced down-regulation of Bcl-X(L), a protein that blocks apoptosis through preventing the release of death-promoting factors from the mitochondria. Mitochondrial proteins the release of which causes anoikis are presently unknown. Similar to what was previously observed by others for keratinocytes and fibroblasts, we show here that anoikis of intestinal epithelial cells does not involve caspase-9, a target of a mitochondrial protein cytochrome c. Furthermore, Smac/Diablo, another mitochondrial pro-apoptotic factor, does not appear to play a role in detachment-dependent apoptosis of these cells either. Instead, anoikis of intestinal epithelial cells is triggered by the release of a mitochondrial protein Omi/HtrA2, an event driven by detachment-induced down-regulation of Bcl-X(L). Moreover, we established that oncogenic ras inhibits anoikis by preventing the release of Omi/HtrA2. This effect of ras required ras-induced down-regulation of a pro-apoptotic protein Bak and could be blocked by an inhibitor of phosphoinositide 3-kinase, a target of Ras that was previously implicated by us in the down-regulation of Bak and blockade of anoikis. We conclude that Omi/HtrA2 is an inducer of anoikis and an important regulator of ras-induced transformation.
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PMID:Oncogenic Ras inhibits anoikis of intestinal epithelial cells by preventing the release of a mitochondrial pro-apoptotic protein Omi/HtrA2 into the cytoplasm. 1646 71

Legionella pneumophila, the agent of human Legionnaire's disease is a Gram-negative, rod-shaped bacterium. During infection, the bacteria invade human cells and replicate intracellularly. L. pneumophila can induce apoptosis in human myeloid and epitheloid cells and this may contribute to the development of pathology and disease. However, the molecular mechanism of apoptosis induction is still uncertain. Here we investigate this process. Legionella efficiently induced apoptosis in myeloid cells, T cells and fibroblasts. Induction of apoptosis involved activation of the initiator caspase-9 and effector caspases. Caspase activity was required for cell death. Analysis of mutant cells showed that the death receptor pathway was not involved in Legionella-induced apoptosis. Surprisingly, caspase activity was found almost exclusively in cells that did not harbor bacteria. Infection with Legionella caused the activation of the pro-apoptotic protein Bax and the release of cytochrome c. Mouse embryonic fibroblasts deficient for Bax and/or Bak were protected from Legionella-induced caspase activation. These results show a clear contribution of the mitochondrial pathway to Legionella-induced apoptosis.
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PMID:Induction of apoptosis by Legionella pneumophila in mammalian cells requires the mitochondrial pathway for caspase activation. 1647 63

The isothiocyanates sulforaphane and PEITC (beta-phenethyl isothiocyanate) as well as the indoles indole-3-carbinol and its condensation product 3,3'-diindolylmethane are known to inhibit cancer cell proliferation and induce apoptosis. In this study, we compared the cell growth inhibitory potential of the four compounds on the p53 wild type human colon cancer cell line 40-16 (p53(+/+)) and its p53 knockout derivative 379.2 (p53(-/-)) (both derived from HCT116). Using sulforhodamin B staining to assess cell proliferation, we found that the isothiocyanates were strongly cytotoxic, whereas the indoles inhibited cell growth in a cytostatic manner. Half-maximal inhibitory concentrations of all four compounds in both cell lines ranged from 5-15 microM after 24, 48 and 72 h of treatment. Apoptosis induction was analyzed by immunoblotting of poly(ADP-ribose)polymerase (PARP). Treatment with sulforaphane (15 microM), PEITC (10 microM), indole-3-carbinol (10 microM) and 3,3'-diindolylmethane (10 microM) induced PARP cleavage after 24 and 48 h in both 40-16 and the 379.2 cell lines, suggestive of a p53-independent mechanism of apoptosis induction. In cultured 40-16 cells, activation of caspase-9 and -7 detected by Western blotting indicated involvement of the mitochondrial pathway. We detected time- and concentration-dependent changes in protein expression of anti-apoptotic Bcl-x(L) as well as pro-apoptotic Bax and Bak proteins. Of note is that for sulforaphane only, ratios of pro- to anti-apoptotic Bcl-2 family protein levels directly correlated with apoptosis induction measured by PARP cleavage. Taken together, we demonstrated that the glucosinolate breakdown products investigated in this study have distinct profiles of cell growth inhibition, potential to induce p53-independent apoptosis and to modulate Bcl-2 family protein expression in human colon cancer cell lines.
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PMID:Comparison of growth inhibition profiles and mechanisms of apoptosis induction in human colon cancer cell lines by isothiocyanates and indoles from Brassicaceae. 1650 Jun 82


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