Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P42574 (caspase-3)
45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since apoptosis is a major contributor to cell loss in medulloblastoma, either spontaneous or induced by radiation and chemotherapy, the apoptotic rate in resection specimens could have prognostic significance. We analysed the apoptotic rate in 58 medulloblastoma resection specimens using an antibody against cleaved caspase 3, a specific marker of apoptotic cell death, and tested its possible prognostic significance. The apoptotic rate varied considerably among medulloblastomas (0.1-25.9%, median 1.1%). Apoptotic cells were relatively evenly distributed in 39 cases, while in 19 cases, an uneven distribution with foci of an increased number of apoptotic cells and their clustering was observed. Clusters of apoptotic cells were found around necrotic areas, while necrotic cells were caspase 3 negative. The apoptotic rate was higher in medulloblastomas with CSF dissemination, tended to be higher in desmoplastic medulloblastomas, but there was no association with age group and sex. In the univariate analysis of overall survival, the apoptotic rate had no prognostic value. The variation in apoptotic rate among medulloblastomas is very likely predominantly associated with variations in tumour microenvironment, as supported by apoptotic cell clustering and rimming around necrotic areas. The apoptotic rate in medulloblastoma resection specimens does not seem to be of prognostic value.
...
PMID:Prognostic significance of apoptosis in medulloblastoma. 1588 92

During the early development of the cerebellum, a burst of granule cell progenitor (GCP) proliferation occurs in the outer external granule layer (EGL), which is sustained mainly by Purkinje cell-derived Sonic Hedgehog (Shh). Shh response is interrupted once GCPs move into the inner EGL, where granule progenitors withdraw proliferation and start differentiating and migrating toward the internal granule layer (IGL). Failure to interrupt Shh signals results in uncoordinated proliferation and differentiation of GCPs and eventually leads to malignancy (i.e., medulloblastoma). The Shh inhibitory mechanisms that are responsible for GCP growth arrest and differentiation remain unclear. Here we report that REN, a putative tumor suppressor frequently deleted in human medulloblastoma, is expressed to a higher extent in nonproliferating inner EGL and IGL granule cells than in highly proliferating outer EGL cells. Accordingly, upregulated REN expression occurs along GCP differentiation in vitro, and, in turn, REN overexpression promotes growth arrest and increases the proportion of p27/Kip1+ GCPs. REN also impairs both Gli2-dependent gene transcription and Shh-enhanced expression of the target Gli1 mRNA, thus antagonizing the Shh-induced effects on the proliferation and differentiation of cultured GCPs. Conversely, REN functional knock-down impairs Hedgehog antagonism and differentiation and sustains the proliferation of GCPs. Finally, REN enhances caspase-3 activation and terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling apoptotic GCP numbers; therefore, the pattern of REN expression, its activity, and its antagonism on the Hedgehog pathway suggest that this gene may represent a restraint of Shh signaling at the outer to inner EGL GCP transitions. Medulloblastoma-associated REN loss of function might withdraw such a limiting signal for immature cell expansion, thus favoring tumorigenesis.
...
PMID:Hedgehog antagonist REN(KCTD11) regulates proliferation and apoptosis of developing granule cell progenitors. 1614 42

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and surgical tumor specimens express SF/HGF and c-Met. Furthermore, c-Met mRNA expression levels statistically significantly correlate with poor clinical outcome. Treatment of medulloblastoma cells with SF/HGF activates c-Met and downstream signal transduction as evidenced by c-Met, mitogen-activated protein kinase, and Akt phosphorylation. SF/HGF induces tumor cell proliferation, anchorage-independent growth, and cell cycle progression beyond the G1-S checkpoint. Using dominant-negative Cdk2 and a degradation stable p27 mutant, we show that cell cycle progression induced by SF/HGF requires Cdk2 function and p27 inhibition. SF/HGF also protects medulloblastoma cells against apoptosis induced by chemotherapy. This cytoprotective effect is associated with reduction of proapoptotic cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 proteins and requires phosphoinositide 3-kinase activity. SF/HGF gene transfer to medulloblastoma cells strongly enhances the in vivo growth of s.c. and intracranial tumor xenografts. SF/HGF-overexpressing medulloblastoma xenografts exhibit increased invasion and morphologic changes that resemble human large cell anaplastic medulloblastoma. This first characterization establishes SF/HGF:c-Met as a new pathway of malignancy with multifunctional effects in human embryonal CNS tumors.
...
PMID:The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. 1623 Mar 98

N-(4-hydroxyphenyl) retinamide (4-HPR, fenretinide) a synthetic retinoid is in clinical trials for the treatment of several malignancies. However, its biological effects and therapeutic value in childhood brain tumor medulloblastoma (MB) has not been investigated. In this study, we report for the first time that fenretinide (2.5-10 microM) induces apoptotic cell death in human MB cells. We observed significant inhibition of cell survival in four MB cell lines (D425MED, D458MED, D283MED and D341MED) as determined by MTT assays. These results were further supported by inhibition of anchorage-independent colony formation in soft agar. Fenretinide-induced decrease in cell viability was in part due to activation of caspase-3 dependent cell death, which was further supported by the cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), a caspase-3 substrate. Cell death was partially prevented by the antioxidant, l-ascorbic acid suggesting that free radical intermediates might be involved in fenretinide effects. These results suggest that pharmacologically achievable concentrations of fenretinide are effective in killing MB cells and thus show its therapeutic potential to treat human MB.
...
PMID:Anticancer effects of fenretinide in human medulloblastoma. 1639 27

Human parathyroid hormone-related protein (hPTHrP), identified in patients with paraneoplastic hypercalcemia and expressed by different cell types during development and adult life, plays important roles in many human neoplasms. Immunohistochemical and RT-PCR analyses of hPTHrP and human parathyroid hormone receptor type 1 (PTHR-1) in primary medulloblastoma confirmed their expression in both classic and desmoplastic variants at RNA and protein levels. To evaluate the functional role of hPTHrP, DAOY and D283 medulloblastoma and U87MG glioma cells, expressing high levels of hPTHrP and PTHR-1, were treated with anti-sense oligonucleotides for hPTHrP. Anti-sense treatment produced in all cell lines a decrease of cell proliferation and clonogenic activity and an increase of apoptosis, while addition of exogenous hPTHrP (1-37) prevented these effects. Anti-sense induced the increase of Caspase-3, Fas (CD95) mRNAs and Bax/Bcl-2 mRNA ratio after 12 h of cell treatment. Exogenous hPTHrP (1-37) increased intracellular Ca(2+) concentration in DAOY cells as revealed by FURA. Anti-sense treated cells showed a significant decrease of steady-state levels of intracellular Ca(2+), which was reverted by addition of exogenous hPTHrP (1-37). This study indicates that hPTHrP and PTHR-1 are expressed in medulloblastoma and could promote tumor growth, protecting cells from apoptosis.
...
PMID:Human parathyroid hormone-related protein and human parathyroid hormone receptor type 1 are expressed in human medulloblastomas and regulate cell proliferation and apoptosis in medulloblastoma-derived cell lines. 1737 45

Japanese encephalitis virus (JEV) causes severe neurological diseases with a high fatality rate. Clinical, neurophysiological and radiological features of Japanese encephalitis JE patients showed that JEV infection resulted in widespread involvement of the nervous system, including thalamus, basal ganglia, brainstem, cerebellum, cerebral cortex and spinal cord. In this study, we characterized the apoptotic effect of JEV infection and its viral proteins on the TE671 human medulloblastoma cells. JEV replicated in TE671 cells, inducing caspase 3-mediated apoptosis in MOI- and time-dependent manners. Of viral proteins, co-expression of JEV NS3 protease with NS2B cofactor significantly induced higher degrees of apoptosis and triggered higher caspase 3 activities than single expression of E, NS1, NS2B or NS3 protease in human medulloblastoma cells. Moreover, JEV NS2B-NS3 protease induced reduction of mitochondrial membrane potential and release of mitochondrial cytochrome C, which were responsible for the mitochondria-mediated apoptosis. In addition, the production of reactive oxygen species production and activation of ASK1-p38 MAPK signaling pathway might be associated with JEV NS2B-NS3 protease-induced mitochondria-mediated apoptosis. The results demonstrated that the JEV infection and the co-expression of JEV NS3 protease with NS2B cofactor induced caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells, being valuable insight for cellular and molecular levels of JEV pathogenesis.
...
PMID:Japanese encephalitis virus NS2B-NS3 protease induces caspase 3 activation and mitochondria-mediated apoptosis in human medulloblastoma cells. 1946 24

Medulloblastoma is the most common malignant cancer of the central nervous system in children. AKT kinases are part of a survival pathway that has been found to be significantly elevated in medulloblastoma. This pathway is a point of convergence for many growth factors and controls cellular processes that are critical for tumor cell survival and proliferation. The alkyl-phospholipid perifosine [octadecyl-(1,1-dimethyl-4-piperidylio) phosphate] is a small molecule inhibitor in clinical trials in peripheral cancers which acts as a competitive inhibitor of AKT kinases. Medulloblastoma cell cultures were used to study the effects of perifosine response in preclinical studies in vitro. Perifosine treatment led to the rapid induction of cell death in medulloblastoma cell lines, with pronounced suppression of phosphorylated AKT in a time-dependent and concentration-dependent manner. LD(50) concentrations were established using viability assays for perifosine, cisplatin, and etoposide. LD(50) treatment of medulloblastoma cells with perifosine led to the cleavage of caspase 9, caspase 7, caspase 3, and poly-ADP ribosylation protein, although caspase 8 was not detectable. Combination single-dose treatment regimens of perifosine with sublethal doses of etoposide or irradiation showed a greater than additive effect in medulloblastoma cells. Lower perifosine concentrations induced cell cycle arrest at the G(1) and G(2) cell cycle checkpoints, accompanied by increased expression of the cell cycle inhibitor p21(cip1/waf1). Treatment with p21 small interfering RNA prevented perifosine-induced cell cycle arrest. These findings indicate that perifosine, either alone or in combination with other chemotherapeutic drugs, might be an effective therapeutic agent for the treatment of medulloblastoma.
...
PMID:The alkylphospholipid perifosine induces apoptosis and p21-mediated cell cycle arrest in medulloblastoma. 1988 60

Medulloblastomas are the most frequent malignant brain tumors in children. Sunitinib is an oral multitargeted tyrosine kinase inhibitor used in clinical trials as an antiangiogenic agent for cancer therapy. In this report, we show that sunitinib induced apoptosis and inhibited cell proliferation of both a short-term primary culture (VC312) and an established cell line (Daoy) of human medulloblastomas. Sunitinib treatment resulted in the activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase and upregulation of proapoptotic genes, Bak and Bim, and inhibited the expression of survivin, an antiapoptotic protein. Sunitinib treatment also downregulated cyclin E, cyclin D2, and cyclin D3 and upregulated p21Cip1, all of which are involved in regulating cell cycle. In addition, it inhibited phosphorylation of signal transducer and activator of transcription 3 (STAT3) and AKT (protein kinase B) in the tumor cells. Dephosphorylation of STAT3 (Tyr(705)) induced by sunitinib was helped by a reduction in activities of Janus-activated kinase 2 and Src. Additionally, sodium vanadate, an inhibitor of protein tyrosine phosphatases, partially blocked the inhibition of phosphorylated STAT3 by sunitinib. Loss of phosphorylated AKT after sunitinib treatment was accompanied by decreased phosphorylation of downstream proteins glycogen synthase kinase-3beta and mammalian target of rapamycin. Expression of a constitutively activated STAT3 mutant or myristoylated AKT partially blocked the effects of sunitinib in these tumor cells. Sunitinib also inhibited the migration of medulloblastoma tumor cells in vitro. These findings suggest the potential use of sunitinib for the treatment of pediatric medulloblastomas.
...
PMID:Sunitinib induces apoptosis and growth arrest of medulloblastoma tumor cells by inhibiting STAT3 and AKT signaling pathways. 2005 26

Medulloblastoma and neuroblastoma belong to a group of neoplasms designated as primitive neuroectodermal tumors (PNETs). Secreted protein, acidic and rich in cysteine (SPARC) is a matrix-associated glycoprotein that influences a variety of cellular activities in vitro and in vivo. In this study, we provide evidence that expression of SPARC cDNA induces autophagy in PNET cells followed by apoptotic cell death. SPARC-induced autophagy was morphologically characterized by (i) the formation of membrane-bound autophagic vacuoles (AVOs), (ii) increase in the levels of microtubule-associated protein light chain 3 (LC3) and (iii) induction of the lysososmal enzyme cathepsin B. Cathepsin B, in turn induced mitochondrial release of cytochrome c and activated caspase-3, events that signify the onset of apoptotic cell death. In agreement with these observations, inhibition of autophagy by 3-MA reduced AVO formation and LC3 and inhibited apoptosis, suggesting that autophagy has a role in SPARC-mediated apoptosis. Blocking cathepsin B expression with a specific inhibitor of cathepsin B suppressed apoptosis but did not affect autophagy, which suggests that cathepsin B is a molecular link between autophagy and apoptosis. In summary, these findings show that SPARC expression induces autophagy, which results in the elevation of cathepsin B and subsequent mitochondria-mediated apoptosis.
...
PMID:Cathepsin B facilitates autophagy-mediated apoptosis in SPARC overexpressed primitive neuroectodermal tumor cells. 2033 79

Medulloblastoma, a neuroectodermal tumor arising in the cerebellum, is the most common brain tumor found in children. We recently showed that nifurtimox induces production of reactive oxygen species (ROS) and subsequent apoptosis in neuroblastoma cells both in vitro and in vivo. Tetrathiomolybdate (TM) has been shown to decrease cell proliferation by inhibition of superoxide dismutase-1 (SOD1). Since both nifurtimox and TM increase ROS levels in cells, we investigated whether the combination of nifurtimox and TM would act synergistically in medulloblastoma cell lines (D283, DAOY). Genome-wide transcriptional analysis, by hybridizing RNA isolated from nifurtimox and TM alone or in combination treated and control cells (D283) on Affymetrix exon array gene chips was carried out to further confirm synergy. We show that nifurtimox and TM alone and in combination decreased cell viability and increased ROS levels synergistically. Examination of cell morphology following drug treatment (nifurtimox + TM) and detection of caspase-3 activation via Western blotting indicated that cell death was primarily due to apoptosis. Microarray data from cells treated with nifurtimox and TM validated the induction of oxidative stress, as many Nrf2 target genes (HMOX1, GCLM, SLC7A11 and SRXN1) (p<10(-5)) were upregulated. Other genes related to apoptosis, oxidative stress, DNA damage, protein folding and nucleosome formation were differentially involved in cells following treatment with nifurtimox + TM. Taken together, our results suggest nifurtimox and TM act synergistically in medulloblastoma cells in vitro, and that this combination warrants further studies as a new treatment for medulloblastoma.
...
PMID:Antitumor activity of nifurtimox is enhanced with tetrathiomolybdate in medulloblastoma. 2139 73


<< Previous 1 2 3 4 Next >>

---