Mitochondrial DNA depletion in prostate epithelial cells promotes anoikisis resistance and invasion through activation of PI3K/Akt2 (Articolo in rivista)

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  • Mitochondrial DNA depletion in prostate epithelial cells promotes anoikisis resistance and invasion through activation of PI3K/Akt2 (Articolo in rivista) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Alternative label
  • 1Moro L; 2Arbini AA; 3Yao JL; 3di Sant’Agnese PA; 1Marra E; 1Greco M. (2009)
    Mitochondrial DNA depletion in prostate epithelial cells promotes anoikisis resistance and invasion through activation of PI3K/Akt2
    in Cell death and differentiation
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • 1Moro L; 2Arbini AA; 3Yao JL; 3di Sant’Agnese PA; 1Marra E; 1Greco M. (literal)
Pagina inizio
  • 571 (literal)
Pagina fine
  • 583 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 16 (literal)
Rivista
Note
  • PubMe (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 1Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari 70126, Italy; 2Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA 3Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA (literal)
Titolo
  • Mitochondrial DNA depletion in prostate epithelial cells promotes anoikisis resistance and invasion through activation of PI3K/Akt2 (literal)
Abstract
  • 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 GSK3b, 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. (literal)
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