Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Elesclomol is a small-molecule investigational agent that selectively induces apoptosis in cancer cells by increasing oxidative stress. Elesclomol plus paclitaxel was shown to prolong progression-free survival compared with paclitaxel alone in a phase II clinical trial in patients with metastatic melanoma. However, the therapeutic potential of elesclomol in human breast cancer is unknown, and the signaling mechanism underlying the elesclomol effect is unclear. Here, we show that elesclomol alone modestly inhibited the growth of human breast cancer cells but not normal breast epithelial cells. Elesclomol potentiated doxorubicin- or paclitaxel-induced apoptosis and suppression of breast cancer cell growth. While both c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase were activated by elesclomol, elesclomol-induced apoptosis was only in part mediated by JNK1. The additive effect of elesclomol on chemotherapy drug-induced apoptosis was associated with increases in cleaved caspase-3, p21(Cip1), and p27(Kip1) and decreases in the Inhibitor of Apoptosis Protein levels and NF-kappaB activity. We also found that Akt/Hsp70 survival signaling was induced by elesclomol, which may reflect a cellular feedback mechanism. Blockade of Akt activation using a small-molecule inhibitor enhanced elesclomol-elicited apoptosis, while expression of a hyperactive Akt abolished the elesclomol effect. These data suggest that elesclomol's interaction with conventional chemotherapeutic and Akt-targeting agents may be exploited to induce apoptosis in breast cancer cells, and clinical trials of combined treatment of elesclomol and chemotherapy drugs or Akt-targeting agents in breast cancer patients, especially the estrogen receptor negative subgroup, may be warranted.
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PMID:Elesclomol, counteracted by Akt survival signaling, enhances the apoptotic effect of chemotherapy drugs in breast cancer cells. 1960 69

Free fatty acids (FFA) induce hepatocyte lipoapoptosis by a c-Jun N-terminal kinase (JNK)-dependent mechanism. However, the cellular processes by which JNK engages the core apoptotic machinery during lipotoxicity, especially activation of BH3-only proteins, remain incompletely understood. Thus, our aim was to determine whether JNK mediates induction of BH3-only proteins during hepatocyte lipoapoptosis. The saturated FFA palmitate, but not the monounsaturated FFA oleate, induces an increase in PUMA mRNA and protein levels. Palmitate induction of PUMA was JNK1-dependent in primary murine hepatocytes. Palmitate-mediated PUMA expression was inhibited by a dominant negative c-Jun, and direct binding of a phosphorylated c-Jun containing the activator protein 1 complex to the PUMA promoter was identified by electrophoretic mobility shift assay and a chromatin immunoprecipitation assay. Short hairpin RNA-targeted knockdown of PUMA attenuated Bax activation, caspase 3/7 activity, and cell death. Similarly, the genetic deficiency of Puma rendered murine hepatocytes resistant to lipoapoptosis. PUMA expression was also increased in liver biopsy specimens from patients with non-alcoholic steatohepatitis as compared with patients with simple steatosis or controls. Collectively, the data implicate JNK1-dependent PUMA expression as a mechanism contributing to hepatocyte lipoapoptosis.
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PMID:JNK1-dependent PUMA expression contributes to hepatocyte lipoapoptosis. 1963 43

Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has been shown to promote apoptosis in cancer cells. However, the role of EGCG in endothelial cells following ischemia/reperfusion (I/R) injury remains unclear. In the present study, we investigated the mechanisms by which EGCG enhances I/R-induced cell growth inhibition and apoptosis in human umbilical vein endothelial cells (HUVECs). Our results showed that EGCG treatment caused cell proliferation inhibition during I/R injury, and this effect was associated with increased p27 and p21 levels and reduced cyclin D1 level. Moreover, treatment of cells with EGCG resulted in increase of caspase-3 and Bax and decrease of Bcl-2, enhancing I/R-induced apoptosis. Interestingly, EGCG decreased I/R-induced phosphorylation of AKT and its downstream substrates Foxo1 and Foxo3a and ERK1/2. In contrast, EGCG increased JNK1/2 and c-Jun phosphorylation. Furthermore, both wortamannin (PI3K inhibitor) and U0126 (MEK1/2 inhibitor) markedly enhanced EGCG-induced apoptosis during I/R, whereas SP600125 (JNK inhibitor) attenuated the action of EGCG. Taken together, our study for the first time suggest that EGCG is able to enhance growth arrest and apoptosis of HUVECs during I/R injury, at least in part, through inhibition of AKT and ERK1/2 and activation of JNK1/2 signaling pathways.
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PMID:Epigallocatechin-3-gallate enhances ischemia/reperfusion-induced apoptosis in human umbilical vein endothelial cells via AKT and MAPK pathways. 1966 89

Livin, a novel member of inhibitors of apoptosis protein, is highly expressed in tumor tissues. It is a potential target in tumor therapy. Silencing its gene expression has been found to promote tumor cell apoptosis or increase tumor sensitivity to therapies. This paper studied the effect of livin anti-apoptotic activity and examined its molecular mechanisms. In the study, higher levels of cell apoptosis were measured by FACS in the experiment group with livin expression silenced than that in controls (P < 0.05). After livin gene expression was knocked down, cleaved caspase-3 protein was up-regulated but caspase-3 mRNA expression was almost the same, the phosphorylated JNK1 protein was down-regulated but JNK1 mRNA and total JNK1 protein expression was approximately the same too. The results suggest that livin may exert anti-apoptotic action on SPC-A1 by activating JNK1 signaling pathway and inhibiting caspase-3 activation.
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PMID:Livin abrogates apoptosis of SPC-A1 cell by regulating JNKI signaling pathway. 1969 Sep 82

Prior studies demonstrated that resistance to the ERBB1/2 inhibitor Lapatinib in HCT116 cells was mediated by increased MCL-1 expression. We examined whether inhibition of BCL-2 family function could restore Lapatinib toxicity in Lapatinib adapted tumor cells and enhance Lapatinib toxicity in naive cells. The BCL-2 family antagonist Obatoclax (GX15-070), that inhibits BCL-2/BCL-X(L)/MCL-1 function, enhanced Lapatinib toxicity in parental HCT116 and Lapatinib adapted HCT116 cells. In breast cancer lines, regardless of elevated ERBB1/2 expression, GX15-070 enhanced Lapatinib toxicity within 3-12 h. The promotion of Lapatinib toxicity neither correlated with cleavage of caspase 3 nor was blocked by inhibition caspases; and was not associated with changes in the activities of ERK1/2, JNK1/2 or p38 MAPK but with reduced AKT, mTOR and S6K1 phosphorylation. The promotion of Lapatinib toxicity by GX15-070 correlated with increased cytosolic levels of apoptosis inducing factor (AIF) and expression of ATG8 (LC3), and the formation of large vesicles that intensely stained for a transfected LC3-GFP construct. Knock down of the autophagy regulatory proteins ATG5 or Beclin1 suppressed the induction of LC3-GFP vesicularization and significantly reduced cell killing, whereas knock down of MCL-1 and BCL-X(L) enhanced the induction of LC3-GFP vesicularization and significantly enhanced cell killing. Knockdown of Beclin1 and AIF abolished cell killing. Collectively, our data demonstrate that Obatoclax mediated inhibition of MCL-1 rapidly enhances Lapatinib toxicity in tumor cells via a toxic form of autophagy and via AIF release from the mitochondrion.
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PMID:Inhibition of MCL-1 enhances lapatinib toxicity and overcomes lapatinib resistance via BAK-dependent autophagy. 1990 22

Evidence shows that women have lower tumour necrosis factor-alpha (TNF-alpha) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17beta-estradiol (E(2)) and estrogen receptor alpha (ERalpha) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERalpha H9c2 myocardial cells and ERalpha-transfected primary cardiomyocytes overexpressing ERalpha. We found that LPS challenge activated JNK1/2, and then induced IkappaB degradation, NFkappaB activation, TNF-alpha up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E(2), membrane-impermeable BSA-E(2) and/or Dox, which induces ERalpha overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IkappaB degradation, NFkappaB activation and pro-apoptotic proteins (e.g. TNF-alpha, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E(2), BSA-E(2) and ERalpha overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E(2), BSA-E(2) and ERalpha expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-alpha expression and cardiomyocyte apoptosis through activation of Akt.
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PMID:Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necresis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. 2019 85

Recent studies have shown that the c-Jun N-terminal kinase (JNK) signaling pathway is involved in dopaminergic neuronal degeneration, and direct blockade of JNK by specific inhibitors may prevent or effectively slow the progression of Parkinson disease (PD). Previous studies have revealed that the natural phenolic compound curcumin can reduce inflammation and oxidation, which makes it a potential therapeutic agent for neurodegenerative diseases. In this study, we investigated whether curcumin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) or 1-methyl-4-phenylpyridnium ion- (MPP(+)) induced dopaminergic neurotoxicity in C57BL/6N mice or SH-SY5Y cells by inhibiting JNK pathways both in vivo and in vitro. Curcumin treatment significantly improved behavioral deficits, and enhanced the survival of tyrosine hydroxylase-positive neurons in the substantia nigra (SN) in the MPTP-induced PD model mice. Most importantly, curcumin treatment significantly inhibited MPTP/MPP(+)-induced phosphorylation of JNK1/2 and c-Jun, and cleaved caspase-3. Our study suggests that the neuroprotective effect of curcumin is not related simply to its antiinflammatory and antioxidant properties, but involves other mechanisms, particularly by targeting the JNK pathways.
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PMID:Curcumin prevents dopaminergic neuronal death through inhibition of the c-Jun N-terminal kinase pathway. 2023 Feb 79

Chondrosarcoma develops as a result of overgrowth of chondrocytes and overproduction of cartilage matrix. It is currently surgically treated, although non-invasive methods are being sought. In this report, pigment epithelium-derived factor (PEDF) induced apoptosis in the chondrosarcoma cell line - JJ012, with upregulation of Bax, Fas, caspase-3 and -6 and downregulation of Bcl-2. Cell cycling was also decreased with decreased expression of p38, p-Akt, p-Erk and JNK1 and increased expression of p73 and E2F1. Furthermore, PEDF increased adhesion of cells to collagen-I, with decreased expression of p-Fak, RhoA and cdc42. Invasion of cells through collagen-I was also reduced by PEDF, with decreased expression of uPAR, MMP-14 and increased expression of PAI-1. These findings seminally indicate that PEDF may have potential as an anti-cancer agent against chondrosarcoma.
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PMID:Anti-chondrosarcoma effects of PEDF mediated via molecules important to apoptosis, cell cycling, adhesion and invasion. 2050 23

Apoptosis is a highly coordinated or programmed cell suicide mechanism in eukaryotes. Histone modification is associated with nuclear events in apoptotic cells. Specifically H2B phosphorylation at serine 14 (Ser14) catalyzed by Mst1 kinase has been linked to chromatin condensation during apoptosis. We report that activation of MAPKs (ERK1/2, JNK1/2 and p38) together with Mst1 and caspase-3 is required for phosphorylation of H2B (Ser14) during ultraviolet B light (UVB)-induced apoptosis. UVB can trigger activation of MAPKs and induce H2B phosphorylation at Ser14 but not acetylation in a time-dependent manner. Inhibition of ERK1/2, JNK1/2 or p38 activity blocked H2B phosphorylation (Ser14). Furthermore, caspase-3 was activated by UVB to regulate Mst1 activity, which phosphorylates H2B at Ser14, leading to chromatin condensation. Full inhibition of caspase-3 activity reduced Mst1 activation and partially inhibited H2B phosphorylation (Ser14), but ERK1/2, JNK1/2 and p38 activities were not affected. Taken together, these data revealed that H2B phosphorylation is regulated by both MAPKs and caspase-3/Mst1 pathways during UVB-induced apoptosis.
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PMID:MAPKs and Mst1/Caspase-3 pathways contribute to H2B phosphorylation during UVB-induced apoptosis. 2060 68

L-DOPA therapy for Parkinson's disease has a double-edge effect on nigrostriatal dopaminergic neurons: L-DOPA increases the intracellular level of dopamine, but it induces neuron cytotoxicity in a concentration-dependent manner. To investigate the molecular signaling mechanisms that underlie the concentration-dependent effects of L-DOPA on cell viability, the activities of mitogen-activated protein kinases (MAPKs) and apoptotic enzymes were measured in rat adrenal pheochromocytoma (PC12) cells in the presence of a low concentration (20 muM) and high concentrations (100-200 muM) of L-DOPA. At the low concentration, L-DOPA was not cytotoxic and its presence increased the activities of extracellular signal-regulated kinase (ERK)1/2, p38 MAPK, BadSer112, Bcl-2, and caspase-12. At the high concentrations, L-DOPA was cytotoxic and stimulated the activities of ERK1/2, p38 MAPK, c-Jun N-terminal kinase (JNK)1/2, BadSer155, caspase-12 and caspase-3. The increased levels of ERK1/2 and BadSer155 in the presence of high concentrations of L-DOPA did not protect against L-DOPA-mediated cytotoxicity. In addition, the levels of L-type Ca(2+) channel-sensitive intracellular cyclic AMP (cAMP) and Ca(2+) were elevated in the presence of L-DOPA, and the increase in the levels of intracellular cAMP may also play a role in cellular viability, since cAMP levels and cytotoxicity increased in parallel with L-DOPA concentrations and the addition of forskolin in the medium increased cytotoxicity in a concentration-dependent manner. These results suggest that, at a low and non-toxic concentration, L-DOPA may promote cell survival by increasing the activities of ERK1/2, BadSer112 and Bcl-2, while, at high concentrations, L-DOPA activates the caspase-3 cell death enzyme through the JNK1/2 and p38 MAPK signaling pathways as well as endoplasmic reticulum stress that activates caspase-12. Intracellular cAMP levels may also play a role here. The results may lead to an effective therapy for Parkinson's disease.
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PMID:Mechanisms of L-DOPA-induced cytotoxicity in rat adrenal pheochromocytoma cells: implication of oxidative stress-related kinases and cyclic AMP. 2067 Jun 75


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