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

HL-60/Bcr-Abl cells, with ectopic expression of p185 Bcr-Abl tyrosine kinase (TK), and K562 cells, with endogenous expression of p210 Bcr-Abl TK, display a high degree of resistance against antileukemic drug-induced apoptosis (G. Fang et al., Blood, 96: 2246-2256, 2000). Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less toxic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytosolic accumulation of cytochrome c and cleavage and activities of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. GA or 17-AAG down-regulated intracellular Bcr-Abl and c-Raf protein levels, as well as reduced Akt kinase activity. Similar to Raf-1, v-Src, and Her-2-neu, Bcr-Abl TK has chaperone association with heat shock protein 90 (Hsp90). By binding and inhibiting Hsp90, GA or 17-AAG treatment shifted the binding of Bcr-Abl from Hsp90 to Hsp70 and induced the proteasomal degradation of Bcr-Abl, because cotreatment with proteasome inhibitor PSC341 reduced both GA (or 17-AAG)-mediated down-regulation of Bcr-Abl levels and inhibited apoptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.
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PMID:Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts. 1128 Jul 26

Alterations in the regulation of apoptosis may contribute to the pathogenesis of cancer and resistance of tumor cells to chemotherapy. In mammalian cells, nonreceptor-mediated apoptosis occurs predominantly via assembly of a cytochrome c-dependent apoptosome complex containing caspase-9 and apoptotic protease-activating factor-1 (Apaf-1). We show here that cytosolic extracts from human ovarian carcinoma cell lines and primary ovarian tumor samples are deficient in their ability to activate procaspase-9 in the presence of cytochrome c and dATP when compared with control extracts. SKOV3, a human ovarian carcinoma cell line with diminished apoptosome activity, was significantly more resistant to chemotherapy-induced apoptosis than cell lines with functional Apaf-1 activity. This dysfunctional apoptosome activity was not explained by reduced expression levels of caspase-9 or Apaf-1. Moreover, expression levels of known inhibitors of the apoptosome, including heat shock protein 70, heat shock protein 90, or X-linked inhibitor of apoptosis, did not correlate with functional activity of the apoptosome. SKOV3, an ovarian cancer cell line with dysfunctional apoptosome activity, retains the ability to form the Apaf-1 oligomer; however, there is a diminished amount of caspase-9 in the apoptosome. The reduction in the amount of caspase-9 in the apoptosome in the SKOV3 cell line was associated with diminished caspase-3 activity. Dysfunctional apoptosome activation may contribute both to the pathogenesis of ovarian carcinoma and to chemoresistance.
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PMID:Dysfunctional apoptosome activation in ovarian cancer: implications for chemoresistance. 1183 May 53

There have been conflicting reports of the apoptotic effects of nicotine on human cells and those studies reporting nicotine-induced apoptosis have not unequivocally clarified the molecular mechanisms underlying the effect. However, we found here that human RSa cells, established from embryonic fibroblastic cells doubly infected with Rous sarcoma virus and Simian virus 40, underwent apoptosis when cultured with medium containing 0.06-0.6 microM nicotine. The apoptosis was assessed by cellular DNA fragmentation and caspase-3 protease activation. Viability of RSa cells was reduced by nicotine treatment, as analyzed by MTT assay and the reduction was lessened by combination treatment with a caspase-3 inhibitor, acetyl-L-aspartyl-L-glutamyl-L-valyl-L-aspart-1-al (Ac-DEVD-CHO). Levels of expression of heat shock protein 90 alpha (Hsp90 alpha) were found to be increased 20 min after the nicotine treatment, as analyzed by polymerase chain reaction-based mRNA differential display after Northern blotting analysis of mRNA amounts. Cellular contents of Hsp90 alpha were furthermore increased in the nicotine-treated RSa cells, as quantitated by Western immunoblot analysis. By contrast, in RSa cells treated with nicotine in combination with geldanamycin (GA), an inhibitor of Hsp90 alpha function, DNA fragmentation was not detected and caspase-3 protease activity levels were the same as those of mock-treated cells. Nicotine-induced caspase-3 activation and Hsp90 alpha expression, as well as suppression of the induction by GA, were also observed in a xeroderma pigmentosum patient-derived cell line, XP2OS cells. Thus, it was suggested that nicotine induces apoptosis, possibly via Hsp90 alpha expression, in human cells tested.
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PMID:Involvement of human heat shock protein 90 alpha in nicotine-induced apoptosis. 1211 84

To find novel pharmacological tools useful for analyzing the molecular mechanism of apoptosis from natural resources, in the present study, we examined the activity of IC101, a cyclic depsipeptide isolated from Streptomyces sp. MJ202-72F3, to induce apoptosis in the L1210 cell line. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IC101 caused a concentration-dependent cell death with a 50% effective concentration value of 20 nM. Cell shrinkage, chromatin condensation, a typical DNA ladder pattern, and up-regulation of cleaved caspase-3 expression, which were biochemical characteristics of apoptosis, were induced by IC101. It also was observed that IC101 caused a concentration-dependent dephosphorylation of Akt and Bad without affecting phosphatidylinositol-3 kinase, an upstream molecule of Akt. IC101 dephosphorylated the 90-kDa protein, as assayed by immunblotting of the cell extract by using anti-phosphotyrosine antibody. To identify the 90-kDa protein, immunoprecipitation and direct nano-flow liquid chromatography-tandem mass spectrometry (LC-MS) were performed to demonstrate that this protein was heat shock protein 90 (HSP90). Consistently, it was observed that IC101 induced the HSP90 tyrosine dephosphorylation by immunoblot analysis of immunoprecipitates with anti-HSP90 antibody using anti-phosphotyrosine antibody. IC101 caused the degradation of Raf-1, which formed a complex with HSP90. The HSP90-ATP binding also was inhibited by IC101 in a noncompetitive manner. An interaction of HSP90 with Akt was shown to be inhibited by IC101 in a concentration-dependent manner. These results suggest that IC101 dephosphorylates Akt through an inhibition of HSP90 functions, resulting in the interaction with Akt to induce apoptotic cell death of L1210 cells.
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PMID:IC101 induces apoptosis by Akt dephosphorylation via an inhibition of heat shock protein 90-ATP binding activity accompanied by preventing the interaction with Akt in L1210 cells. 1516 34

Geldanamycin (GA) binds to heat shock protein 90 (Hsp90) and interferes with its function which is to protect various cellular proteins involved in signaling, growth control, and survival from ubiquitination and subsequent degradation by the proteasome. Recently, we demonstrated that GA inhibited migration of glioma cells in vitro associated with downregulation of hypoxia-inducible factor (HIF-1 alpha) and phosphorylation of focal adhesion kinase (FAK) (Zagzag et al., 2003, J Cell Physiol 196:394-402). Here, we have investigated the mechanisms through which GA treatment of the T98G glioma cell line induces apoptosis. We found that GA treatment induced cell death in a caspase-dependent manner through activation of caspase-3 and PARP cleavage together with release of cytochrome c and apoptosis inducing factor (AIF) from the mitochondria. Use of synchronized T98G cells showed that GA treatment of glioma cells during S-phase enhanced cytotoxicity followed by M-phase arrest, resulting in mitotic catastrophe. In addition, apoptosis was associated with the downregulation of the survival protein, phosphorylated Akt (pAkt), an important signaling protein in the PI3K pathway, that is overexpressed in many cancers including gliomas. Given that many glioma tumors show deregulation of the PI3K signaling pathway, either through loss of the tumor suppressor protein PTEN or overexpression of the growth factor EGFR, the ability to identify different subsets of patients using simple immunohistochemistry for the presence of absence of pAkt could enable selection of the appropriate kinase inhibitor, such as GA, for drug therapy. Based on our data presented here, GA or its analogs may have potential in the treatment of glioma.
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PMID:Geldanamycin induces mitotic catastrophe and subsequent apoptosis in human glioma cells. 1538 45

The heat shock protein 90 co-chaperone p23 has recently been shown to be up-regulated in cancer cells and down-regulated in atheroschlerotic plaques. We found that p23 is degraded during apoptosis induced by several stimuli, including Fas and TNFalpha-receptor activation as well as staurosporine treatment. Caspase inhibition protected p23 from degradation in several cell lines. In addition, recombinant caspase-3 and 8 cleaved p23 at Asp 142 generating a degradation product of 18 kDa as seen in apoptotic cells. Truncated p23 is further degraded in a proteasome dependent process during apoptosis. Furthermore, we found that the anti-aggregating activity of truncated p23 was reduced compared to full length p23 indicating that caspase mediated p23 degradation contributes to protein destabilisation in apoptosis.
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PMID:The co-chaperone p23 is degraded by caspases and the proteasome during apoptosis. 1603 4

Inhibition of heat shock protein 90 (Hsp90) has emerged as a novel intervention for the treatment of solid tumors and leukemias. Here, we report that F(1)F(0)-ATP synthase, the enzyme responsible for the mitochondrial production of ATP, is a co-chaperone of Hsp90. F(1)F(0)-ATP synthase co-immunoprecipitates with Hsp90 and Hsp90-client proteins in cell lysates of MCF-7, T47D, MDA-MB-453, and HT-29 cancer cells. Inhibition of F(1)F(0)-ATP synthase by efrapeptins results in the disruption of the Hsp90 complexing with its substrate proteins and, in most cases, in the degradation of the latter. Hsp90-client proteins affected by the inhibition of F(1)F(0)-ATP synthase included ERalpha, mutated p53 (m.p53), Hsp70, Hsp27, and caspase-3 but not Raf-1. This is the first report identifying caspase-3 as a substrate protein of Hsp90. Unlike typical Hsp90 inhibitors, efrapeptin treatment triggers Hsp70 downregulation in parallel with depletion of Hsp90. This suggests that suppression of Hsp90 chaperone function through inhibition of F(1)F(0)-ATP synthase does not result in activation of transcription factor HSF-1, a generally unfavorable consequence of anti-cancer treatments based on Hsp90 inhibition.
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PMID:F1F0-ATP synthase functions as a co-chaperone of Hsp90-substrate protein complexes. 1668 2

Apoptosis is a highly conserved process that plays an important role in controlling tissue development, homeostasis, and architecture. Dysregulation of apoptosis is a hallmark of numerous human pathologies including hypertension. In the present work we studied the effect of hypertension on apoptosis and the expression of several apoptotic signaling and/or regulatory proteins in four functionally and metabolically distinct muscles. Specifically, we examined these markers in soleus, red gastrocnemius, white gastrocnemius, and left ventricle (LV) of 20-wk-old normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Compared with WKY rats SHR had a significantly greater heart weight, LV weight, and mean arterial pressure. In general, SHR skeletal muscle had increased Bax protein, procaspase-3 protein, caspase-3 activity, cleaved poly(ADP-ribose) polymerase protein, and DNA fragmentation as well as decreased Bcl-2 protein and a lower Bcl-2-to-Bax ratio. Subcellular distribution studies demonstrated increased levels of apoptosis-inducing factor protein in cytosolic or nuclear extracts as well as elevated nuclear Bax protein in SHR skeletal muscle. Moreover, heat shock protein 70 in red gastrocnemius and soleus was significantly correlated to several apoptotic factors. With the exception of lower heat shock protein 90 levels in SHR no additional differences in any apoptotic markers were observed in LV between groups. Collectively, this report provides the first evidence that apoptotic signaling is altered in skeletal muscle of hypertensive animals, an effect that may be mediated by both caspase-dependent and -independent mechanisms. This proapoptotic state may provide some understanding for the morphological and functional abnormalities observed in skeletal muscle of hypertensive animals.
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PMID:Increased DNA fragmentation and altered apoptotic protein levels in skeletal muscle of spontaneously hypertensive rats. 1677 6

The molecular chaperone heat shock protein 90 (Hsp90) affects the function of many oncogenic signaling proteins including nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) expressed in anaplastic large cell lymphoma (ALCL). While ALK-positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin (GA) analog, 17-allylamino-17-demethoxygeldanamycin (17-AAG), the proteomic effects of these drugs on ALK-positive ALCL cells are unpublished. In this study, we investigated the cellular, biologic, and proteomic changes occurring in ALK-positive ALCL cells in response to GA treatment. GA induced G2/M cell cycle arrest and caspase-3-mediated apoptosis. Furthermore, quantitative proteomic changes analyzed by cleavable isotope-coded affinity tag-LC-MS/MS (cICAT-LC-MS/MS) identified 176 differentially expressed proteins. Out of these, 49 were upregulated 1.5-fold or greater and 70 were downregulated 1.5-fold or greater in GA-treated cells. Analysis of biological functions of differentially expressed proteins revealed diverse changes, including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism. Pathway analysis revealed changes in MAPK, WNT, NF-kappaB, TGFbeta, PPAR, and integrin signaling components. Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in ALK-positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects.
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PMID:Proteome-wide changes induced by the Hsp90 inhibitor, geldanamycin in anaplastic large cell lymphoma cells. 1761 Feb 8

Resistance to imatinib can occur in patients with chronic myelogenous leukemia (CML). In this study, we report mechanisms of action of histone deacetylase (HDAC) inhibitor, depsipeptide (FK228) in BCR/ABL-expressing cell lines and its effectiveness in imatinib-resistant cells from patients with blast crisis of CML. FK228 potently induced apoptosis of TF-1 BCR/ABL, K562, and H7 BCR/ABL cells. We found that histone H4, BCR/ABL, heat shock protein 90 (HSP-90), p53, focal adhesion kinase (FAK), paxillin, and retinoblastoma protein (Rb) were acetylated in the treated cells. Cells were also blocked in G(2)/M phase of the cell cycle and activity of mitogen-activated protein kinase (MAPK) was blocked, but p38MAPK (p38) was activated. Inhibitor of apoptosis proteins (IAPs) were suppressed, and common results of apoptotic induction were observed, such as caspase-3, caspase-9, and poly(ADP-ribose) polymerase (PARP) activation. Although p38 was phosphorylated after FK228 treatment, histone H4 acetylation, caspase-3 activation, and apoptosis were not inhibited by treatment with the p38 inhibitor SB203580. We also found that human telomerase reverse transcriptase (hTERT) ShRNA-transfected cells demonstrated decreased FK228-induced apoptosis. Of clinical relevance, FK228-induced apoptosis of imatinib-resistant primary cells from patients with CML, who had progressed to blast crisis (BC) while receiving therapy with imatinib. In conclusion, FK228 potently induces apoptosis of CML cells by acetylation and degradation of BCR/ABL protein. Our study suggests how FK228 may mediate its effects on imatinib-resistant CML cells.
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PMID:Depsipeptide (FK228) preferentially induces apoptosis in BCR/ABL-expressing cell lines and cells from patients with chronic myelogenous leukemia in blast crisis. 1761 Mar 80


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