Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary glioblastomas (GBMs) commonly overexpress the oncogene epidermal growth factor receptor (EGFR), which leads to increased Ras activity. FTA, a novel Ras inhibitor, produced both time- and dose-dependent caspase-mediated apoptosis in GBM cell lines. EGFR-mediated increase in 3H-thymidine uptake was inhibited by FTA. FACS analysis was performed to determine the percent of apoptotic cells. The sub-Go population of GBM cells was increased from 4.5 to 13.8% (control) to over 45-53.6% in FTA-treated cells within 24 h. Furthermore, FTA also increased the activities of both caspase-3 and -9, and PARP cleavage. Treatment of GBMs with FTA before or after EGF addition to the cultures blocked phosphorylation of Akt and mitogen-activated protein kinases (MAPK). FTA also significantly reduced the amount of EGF-induced Ras-GTP as reflected by a decrease in the level of Ras bound to Raf-RBD-GST. This study demonstrates that inhibition of Ras methylation may provide a therapeutic target for the treatment of GBMs overexpressing EGFR.
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PMID:Farnesylthiosalicylic acid induces caspase activation and apoptosis in glioblastoma cells. 1623 32

The group B streptococcus (GBS) is an opportunistic bacterial pathogen with the ability to cause invasive disease. While the ability of GBS to invade a number of host-cell types has been clearly demonstrated, the invasion process is not well understood at the molecular level. What has been well established is that modulation of host-cell actin microfilaments is essential for GBS invasion to occur. Phosphoinositide-3 kinase (PI3K) is a key regulator of the cytoskeleton in eukaryotic cells. Our goal in this investigation was to explore the role of the PI3K/Akt signalling pathway in epithelial cell invasion by GBS. The epithelial cell invasion process was mimicked using the HeLa 229 cell-culture model. Treating HeLa cells with chemical inhibitors of PI3K, Akt or Ras prior to bacterial infection inhibited GBS invasion but not attachment; treatment with 30 microM LY294002 (PI3K inhibitor) reduced GBS invasion by 75%, 20 microM L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (ICIO) (Akt inhibitor) reduced GBS invasion by 50%, and 10 microM manumycin A (Ras inhibitor) inhibited GBS invasion by 90%. Genetic inactivation of the p85alpha or p110alpha PI3K subunits in HeLa cells also reduced GBS invasion by 55 and 30%, respectively. Western blot analysis revealed that phosphorylation of host-cell Akt and glycogen synthase kinase-3 (GSK-3) occurs in response to GBS infection, and that this is mediated upstream by PI3K. Infection of HeLa cells with GBS triggers pro-survival signalling and protects the HeLa cells from camptothecin-induced caspase-3 cleavage. The results from this investigation show that GBS both requires and activates the PI3K/Akt host-cell signalling pathway during invasion of epithelial cells.
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PMID:Invasion of HeLa cells by group B streptococcus requires the phosphoinositide-3-kinase signalling pathway and modulates phosphorylation of host-cell Akt and glycogen synthase kinase-3. 1804 37

MT477 is a novel quinoline with potential activity in Ras-mutated cancers. In this study, MT477 preferentially inhibited the proliferation of K-ras-mutated human pulmonary (A549) and pancreatic (MiaPaCa-2) adenocarcinoma cell lines, compared with a non-Ras-mutated human lung squamous carcinoma cell line (H226) and normal human lung fibroblasts. MT477 treatment induced apoptosis in A549 cells and was associated with caspase-3 activation. MT477 also induced sub-G1 cell-cycle arrest in A549 cells. Although we found that MT477 partially inhibited protein kinase C (PKC), it inhibited Ras directly followed in time by inhibition of 2 Ras downstream molecules, Erk1/2 and Ral. MT477 also caused a reorganization of the actin cytoskeleton and formation of filopodias in A549 cells; this event may lead to decreased migration and invasion of tumor cells. In a xenograft mouse model, A549 tumor growth was inhibited significantly by MT477 at a dose of 1 mg/kg (P < 0.05 vs vehicle control). Taken together, these results support the conclusion that MT477 acts as a direct Ras inhibitor. This quinoline, therefore, could potentially be active in Ras-mutated cancers and could be developed extensively as an anticancer molecule with this in mind.
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PMID:Novel Ras pathway inhibitor induces apoptosis and growth inhibition of K-ras-mutated cancer cells in vitro and in vivo. 1901 Feb 91

In the rostral ventrolateral medulla (RVLM), angiotensin II-derived superoxide anions, which increase sympathetic nerve activity, induce a pressor response by activating the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK) pathway. The small G protein Ras mediates a caspase-3-dependent apoptotic pathway through p38 MAPK, ERK, and c-Jun N-terminal kinase. We hypothesized that angiotensin II type 1 receptors activate caspase-3 through the Ras/p38 MAPK/ERK/c-Jun N-terminal kinase pathway in the RVLM and that this pathway is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats (SHRSP), a model of human hypertension. The activities of Ras, p38 MAPK, ERK, and caspase-3 in the RVLM were significantly higher in SHRSP (14 to 16 weeks old) than in age-matched Wistar-Kyoto rats (WKY). The mitochondrial apoptotic proteins Bax and Bad in the RVLM were significantly increased in SHRSP compared with WKY. c-Jun N-terminal kinase activity did not differ between SHRSP and WKY. In SHRSP, intracerebroventricular infusion of a Ras inhibitor significantly reduced sympathetic nerve activity and improved baroreflex sensitivity, partially because of inhibition of the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. Intracerebroventricular infusion of a caspase-3 inhibitor also inhibited sympathetic nerve activity and improved baroreflex sensitivity in SHRSP. Intracerebroventricular infusion of an angiotensin II type 1 receptor blocker in SHRSP partially inhibited the Ras/p38 MAPK/ERK, Bax, Bad, and caspase-3 pathway in the RVLM. These findings suggest that in SHRSP, angiotensin II type 1 receptor-activated caspase-3 acting through the Ras/p38 MAPK/ERK pathway in the RVLM might be involved in sympathoexcitation, which in turn plays a crucial role in the pathogenesis of hypertension.
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PMID:Angiotensin II type 1 receptor-activated caspase-3 through ras/mitogen-activated protein kinase/extracellular signal-regulated kinase in the rostral ventrolateral medulla is involved in sympathoexcitation in stroke-prone spontaneously hypertensive rats. 2006 58

Background: The central nervous system plays a vital role in the development of hypertension, but the molecular regulatory mechanisms are not fully understood. This study aimed to explore signaling in the paraventricular nucleus (PVN) which might contribute to renal hypertension. Methods: Renal hypertension model was established by five-sixth nephrectomy operation (5/6Nx) in male Sprague Dawley rats. Ten weeks afterwards, they were random assigned to no treatment, or intracerebroventricular injection (ICV) with artificial cerebrospinal fluid, losartan [angiotensin II receptor type 1 (AT1R) antagonist], farnesylthiosalicylic acid (Ras inhibitor), PD98059 (MEK inhibitor), or SB203580 (p38 inhibitor) and Z-DEVD-FMK (caspase-3 inhibitor). Before and after treatment, physiological and biochemical indices were measured. Immunohistochemistry, western blot and RT-PCR were applied to quantify key components of renin-angiotensin system, apoptosis-related proteins, Ras-GTP, and MAPKs in the PVN samples. TUNEL assay was used to measure the situ apoptosis in PVN. Results: The 5/6Nx rats showed significantly elevated systolic blood pressure, urinary protein excretion, serum creatinine, and plasma norepinephrine (p < 0.05) compared to sham rats. The expression of angiotensinogen, Ang II, AT1R, p-ERK1/2, or apoptosis-promoting protein Bax were 1.08-, 2.10-, 0.74-, 0.82-, 0.83-fold higher in the PVN of 5/6Nx rats, than that of sham rats, as indicated by immunohistochemistry. Western blot confirmed the increased levels of AT1R, p-ERK1/2 and Bax; meanwhile, Ras-GTP and p-p38 were also found higher in the PVN of 5/6Nx rats, as well as the apoptosis marker cleaved caspase-3 and TUNEL staining. In 5/6Nx rats, ICV infusion of AT1R antagonist, Ras inhibitor, MEK inhibitor or caspase-3 inhibitor could lower systolic blood pressure (20.8-, 20.8-, 18.9-, 14.3%-fold) together with plasma norepinephrine (53.9-, 57.8-,63.3-, 52.3%-fold). Western blot revealed that blocking the signaling of AT1R, Ras, or MEK/ERK1/2 would significantly reduce PVN apoptosis as indicated by changes of apoptosis-related proteins (p < 0.05). AT1R inhibition would cause reduction in Ras-GTP and p-ERK1/2, but not vice versa; such intervention with corresponding inhibitors also suggested the unidirectional regulation of Ras to ERK1/2. Conclusion: These findings demonstrated that the activation of renin-angiotensin system in PVN could induce apoptosis through Ras/ERK1/2 pathway, which then led to increased sympathetic nerve activity and renal hypertension in 5/6Nx rats.
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PMID:Increased Apoptosis in the Paraventricular Nucleus Mediated by AT1R/Ras/ERK1/2 Signaling Results in Sympathetic Hyperactivity and Renovascular Hypertension in Rats after Kidney Injury. 2821 Feb 25

Aloperine (Alo), as a quinolizidine alkaloid extracted from S. alopecuroide, has the positive activities of anti-inflammatory, anti-allergenic, antitumor and anti-viral. However, the role and mechanism of Alo in breast cancer have not been studied yet. In the present study, Alo markedly inhibited the proliferation and suppressed the colony formation ability of the breast cancer cell lines MCF-7 and MDA-MB-231 in a dose-dependent manner by Cell Counting kit-8 and colony formation assays, respectively. In addition, the results of confocal microscopy analysis and flow cytometry detection revealed that Alo induced the apoptosis of MCF-7 and MDA-MB-231 cells, and western blotting indicated that Alo upregulated the protein levels of Bax, caspase-3 and caspase-9, and downregulated the expression of Bcl-2. Furthermore, the results of wound healing, Transwell migration and invasion assays demonstrated that Alo inhibited the migration and invasion of MCF-7 and MDA-MB-231 cells, and reduced the protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. Alo also downregulated the protein expressions of Ras, phosphorylated (p)-Raf proto-oncogene, serine/threonine kinase 1 and p-extracellular signal-regulated kinase 1/2. Furthermore, ISIS 2503, a Ras inhibitor, inhibited colony formation, induced apoptosis, and suppressed the migration and invasion of MCF-7 and MDA-MB-231 cells. These effects were more marked in the presence of ISIS 2503 and Alo, when compared with those of either agent alone. In conclusion, the present study reported a novel use of Alo in inhibiting the proliferation, migration and invasion, and inducing the apoptosis of human breast cancer cells by blocking the Ras signaling pathway.
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PMID:Aloperine inhibits proliferation, migration and invasion and induces apoptosis by blocking the Ras signaling pathway in human breast cancer cells. 3013 40