Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.9.3.1 (cytochrome oxidase)
 8,822 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cyclosporine on certain endothelial cell functions, namely matrix metalloprotease (MMP)-2 and MMP-9 secretion, proliferation, chemotaxis, and morphogenesis, were investigated in vitro, and its effects on angiogenesis were studied in vivo by using the chick embryo chorioallantoic membrane (CAM) model. In vitro, at low noncytotoxic doses (2, 4, 8, and 16 microg/mL), cyclosporine inhibited all these functions in a dose-dependent manner, although MMP-2 secretion was inhibited only at 16 microg/mL. The absence of cytotoxicity was confirmed morphologically and also because inhibition was rapidly reversed as soon as cyclosporine was removed. In vivo, cyclosporine at 0.012 and 0.024 microg per CAM displayed noncytotoxic, dose-dependent antiangiogenic activity. Biochemically, the drug inhibited the activity of the endothelial cell respiratory chain enzymes succinate oxidase and cytochrome-c oxidase, again in a dose-dependent manner. This finding could explain the effects observed in vitro and in vivo. These antiangiogenic properties of low-dose cyclosporine warrant further investigation in certain autoimmune and neoplastic diseases characterized by enhanced angiogenesis.
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PMID:Antiangiogenesis by cyclosporine. 984 77

Neoplastic transformation of prostate epithelium involves aberrant activation of anti-apoptotic and pro-invasive pathways triggered by multiple poorly understood genetic events. We demonstrated earlier that depletion of mitochondrial DNA (mtDNA) induces prostate cancer progression. Here, using normal prostate epithelial PNT1A cells we demonstrate that mtDNA depletion prevents detachment-induced apoptosis (anoikis) and promotes migratory capabilities onto basement membrane proteins through upregulation of p85 and p110 phosphatidylinositol 3-kinase (PI3K) subunits, which results in Akt2 activation and phosphorylation of downstream substrates GSK3beta, c-Myc, MMP-9, Mdm2, and p53. Pharmacological or genetic PI3K inhibition, siRNA-mediated Akt2 depletion, as well as mtDNA reconstitution were sufficient to restore sensitivity to anoikis and curtail cell migration. Moreover, Akt2 activation induced glucose transporter 1 (GLUT1) expression, glucose uptake, and lactate production, common phenotypic changes seen in neoplastic cells. In keeping with these findings, several prostate carcinoma cell lines displayed reduced mtDNA content and increased PI3K/Akt2 levels when compared to normal PNT1A cells, and Akt2 downregulation prevented their survival, migration and glycolytic metabolism. On a tissue microarray, we also found a statistically significant decrease in mtDNA-encoded cytochrome oxidase I in prostate carcinomas. Taken together, these results provide novel mechanistic evidence supporting the notion that mtDNA mutations may confer survival and migratory advantage to prostate cancer cells through Akt2 signaling.
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PMID:Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2. 1907 38