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)

There is increasing evidence suggesting that chondrocyte death may contribute to the progression of osteoarthritis (OA). This study focused on the characterization of signaling cascade during NO-induced cell death in human OA chondrocytes. The NO generator, sodium nitroprusside (SNP), promoted chondrocyte death in association with DNA fragmentation, caspase-3 activation, and down-regulation of Bcl-2. Both caspase-3 inhibitor Z-Asp(OCH3)-Glu(OCH3)-Val-Asp(OCH3)-CH2F and caspase-9 inhibitor Z-Leu-Glu(OCH3)-His-Asp(OCH3)-CH2F prevented the chondrocyte death. Blocking the mitogen-activated protein kinase pathway by the mitogen-activated protein kinase kinase 1/2 inhibitor PD98059 or p38 kinase inhibitor SB202190 also inhibited the SNP-mediated cell death, suggesting possible requirements of both extracellular signal-related protein kinase 1/2 and p38 kinase for the NO-induced cell death. Furthermore, the selective inhibition of cyclooxygenase (COX)-2 by NS-398 or the inhibition of COX-1/COX-2 by indomethacin blocked the SNP-induced cell death. The chondrocyte death induced by SNP was associated with an overexpression of COX-2 protein (as determined by Western blotting) and an increase in PGE2 release. PD98059 and SB202190, but neither Z-DEVD FMK nor Z-LEHD FMK completely inhibited the SNP-mediated PGE2 production. Analysis of interactions between PGE2 and the cell death showed that PGE2 enhanced the SNP-mediated cell death, whereas PGE2 alone did not induce the chondrocyte death. These data indicate that NO-induced chondrocyte death signaling includes PGE2 production via COX-2 induction and suggest that both extracellular signal-related protein kinase 1/2 and p38 kinase pathways are upstream signaling of the PGE2 production. The results also demonstrate that exogenous PGE2 may sensitize human OA chondrocytes to the cell death induced by NO.
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PMID:The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. 1097 59

Recently, statins have been demonstrated to improve cancer-related mortality or prognosis in patients of various cancers. However, the details of the apoptosis-inducing mechanisms remain unknown. This study showed that the induction of apoptosis by statins in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of mevalonate or geranylgeranyl pyrophosphate biosynthesis. In addition, statins decreased the levels of phosphorylated extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin through suppressing Ras prenylation. Furthermore, inhibition of extracellular signal-regulated kinase 1/2 and mammalian target of rapamycin by statins induced Bim expression via inhibition of Bim phosphorylation and ubiquitination and cell-cycle arrest at G1 phase via enhancement of p27 expression. Moreover, combined treatment of U0126, a mitogen-activated protein kinase kinase 1/2 inhibitor, and rapamycin, a mammalian target of rapamycin inhibitor, induced Bim and p27 expressions. The present results suggested that statins induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, enhancing Bim expression, and inducing cell-cycle arrest at G1 phase through inhibition of Ras/extracellular signal-regulated kinase and Ras/mammalian target of rapamycin pathways. Therefore, our findings support the use of statins as potential anticancer agents or concomitant drugs of adjuvant therapy.
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PMID:Statins induce apoptosis through inhibition of Ras signaling pathways and enhancement of Bim and p27 expression in human hematopoietic tumor cells. 2899 Apr 65