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Cellular Oncology
Volume 30, Issue 4, Pages 307-322
http://dx.doi.org/10.3233/CLO-2008-0427

Mitochondrial DNA Depletion Reduces PARP-1 Levels and Promotes Progression of the Neoplastic Phenotype in Prostate Carcinoma

Loredana Moro,1 Arnaldo A. Arbini,2 Ersilia Marra,1 and Margherita Greco1

1Institute of Biomembranes and Bioenergetics, National Research Council (CNR), Bari 70126, Italy
2Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA

Copyright © 2008 Hindawi Publishing Corporation and the authors. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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 (ΔΨm), increased migration onto the basement membrane protein laminin-1, reduced chemosensitivity to paclitaxel (IC50=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 ΔΨm loss, acquisition of invasive cytology, increased motility onto laminin-1, reduced sensitivity to paclitaxel (IC50=~100 nM) and ~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.