Up-regulation of cathepsin B expression and enhanced secretion in mitochondrial DNA-depleted osteosarcoma cells.
BACKGROUND
mtDNA (mitochondrial DNA) mutations that impair oxidative phosphorylation can contribute to carcinogenesis through the increased production of reactive oxygen species and through the release of proteins involved in cell motility and invasion. On the other hand, many human cancers are associated with both the up-regulation and the increased secretion of several proteases and heparanase. In the present study, we tried to determine whether the depletion in mtDNA could modulate the expression and/or the secretion of some lysosomal hydrolases in the 143B osteosarcoma cells, as these mtDNA-depleted cells are characterized by a higher degree of invasiveness than the parental cells.


RESULTS
In comparison with the parental cells, we measured a higher amount of procathepsin B in the conditioned culture medium of the 143B cells lacking mtDNA (rho(0) 143B cells), as well as a rise in the specific activity of intracellular cathepsin B. In addition, we observed an activation of the transcription factor NF-kappaB (nuclear factor kappaB) in the cells devoid of functional mitochondria. Finally, we demonstrated that the down-regulation of the NF-kappaB p65 subunit by RNA interference led to a reduction in cathepsin B expression in rho(0) 143B cells.


CONCLUSIONS
The up-regulation of cathepsin B by NF-kappaB, followed by its secretion into the extracellular environment, might be partly responsible for the previously reported invasiveness of the mtDNA-depleted 143B osteosarcoma cells.
Hamer
Isabelle
I
URPhym, Unité de Recherche en Physiologie Moléculaire, Laboratoire de Chimie Physiologique, Facultés Universitaires N-D de la Paix, Rue de Bruxelles, 61, 5000 Namur, Belgium. isabelle.hamer@fundp.ac.be
Delaive
Edouard
E
Dieu
Marc
M
Abdel-Sater
Fadi
F
Mercy
Ludovic
L
Jadot
Michel
M
Arnould
Thierry
T
D002401:Cathepsin B / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D012516:Osteosarcoma / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000172:deficiency / Q000187:drug effects; D015854:Up-Regulation / Q000235:genetics*
D004272:DNA, Mitochondrial; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D002401:Cathepsin B