Mitochondrial DNA depletion reduces PARP-1 levels and promotes progression of the neoplastic phenotype in prostate carcinoma.
Mitochondrial dysfunction resulting from mitochondrial DNA (mtDNA) mutations and/or depletion has been correlated with cancer progression and drug resistance. To investigate the role of mtDNA in prostate cancer progression, we used LNCaP and PC-3 prostate carcinoma cells as experimental model. Compared to minimally invasive androgen-dependent LNCaP cells, highly invasive androgen-independent PC-3 cells, as well as androgen-independent DU145 and C4-2 cells, exhibited significantly reduced mtDNA content. In PC-3 cells, reduction of mtDNA was accompanied by decreased mitochondrial membrane potential (DeltaPsi(m)), increased migration onto the basement membrane protein laminin-1, reduced chemosensitivity to paclitaxel (IC(50)=110 nM vs. 22 nM) and decreased expression of poly(ADP-ribose) polymerase (PARP)-1. To investigate the relationship between mtDNA depletion and these phenotypic characteristics, we established mtDNA-depleted LNCaP cells [Rho(-)] by long-term exposure to ethidium bromide or treated wild-type LNCaP cells with a mitochondrial ionophore, carbonyl cyanide m-chlorophenylhydrazone. Both manipulations resulted in DeltaPsi(m) loss, acquisition of invasive cytology, increased motility onto laminin-1, reduced sensitivity to paclitaxel (IC(50)= approximately 100 nM) and approximately 75% reduction in PARP-1 protein levels, resembling PC-3 cells. Overall, these results provide novel evidence demonstrating that mtDNA depletion in early prostate carcinoma may contribute to the acquisition of a more invasive phenotype that is less sensitive to paclitaxel-induced apoptosis.
Moro
Loredana
L
Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari 70126, Italy. l.moro@ibbe.cnr.it
Arbini
Arnaldo A
AA
Marra
Ersilia
E
Greco
Margherita
M
D000728:Androgens / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004272:DNA, Mitochondrial / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004996:Ethidium / Q000494:pharmacology; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
D000728:Androgens; D002273:Carcinogens; D004272:DNA, Mitochondrial; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004996:Ethidium; D017239:Paclitaxel