Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2.
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.
Moro
L
L
Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari, Italy.
Arbini
A A
AA
Yao
J L
JL
di Sant'Agnese
P A
PA
Marra
E
E
Greco
M
M
D023102:Anoikis / Q000187:drug effects / Q000502:physiology*; D015139:Blotting, Southern; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051545:Cyclooxygenase 1 / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D004996:Ethidium / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011467:Prostate / Q000166:cytology* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D046888:Tissue Array Analysis
D004272:DNA, Mitochondrial; D006861:Hydrogen Peroxide; D051545:Cyclooxygenase 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D004996:Ethidium