Stimulation of mitochondrial activity by p43 overexpression induces human dermal fibroblast transformation.
Mitochondrial dysfunctions are frequently reported in cancer cells, but their direct involvement in tumorigenesis remains unclear. To understand this relation, we stimulated mitochondrial activity by overexpression of the mitochondrial triiodothyronine receptor (p43) in human dermal fibroblasts. In all clones, this stimulation induced morphologic changes and cell fusion in myotube-like structures associated with the expression of several muscle-specific genes (Myf5, desmin, connectin, myosin, AchRalpha). In addition, these clones displayed all the in vivo and in vitro features of cell transformation. This phenotype was related to an increase in c-Jun and c-Fos expression and extinction of tumor suppressor gene expression (p53, p21WAF1, Rb3). Lastly, reactive oxygen species (ROS) production was increased in positive correlation to the stimulation of mitochondrial activity. The direct involvement of mitochondrial activity in this cell behavior was studied by adding chloramphenicol, an inhibitor of mitochondrial protein synthesis, to the culture medium. This inhibition resulted in partial restoration of the normal phenotype, with the loss of the ability to fuse, a strong decrease in muscle-specific gene expression, and potent inhibition of the transformed phenotype. However, expression of tumor suppressor genes was not restored. Similar results were obtained by using N-acetylcysteine, an inhibitor of ROS production. These data indicate that stimulation of mitochondrial activity in human dermal fibroblasts induces cell transformation through events involving ROS production.
Grandemange
Stéphanie
S
UMR 866, Différenciation Cellulaire et Croissance (INRA-UMII-ENSAM), Unité d'Endocrinologie Cellulaire, Institut National de la Recherche Agronomique, Montpelier, France.
Seyer
Pascal
P
Carazo
Angel
A
Bécuwe
Philippe
P
Pessemesse
Laurence
L
Busson
Muriel
M
Marsac
Cécile
C
Roger
Pascal
P
Casas
François
F
Cabello
Gérard
G
Wrutniak-Cabello
Chantal
C
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002701:Chloramphenicol / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D024101:Mitochondrial Proteins; D010444:Peptide Elongation Factor Tu / Q000096:biosynthesis*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
D000951:Antigens, Neoplasm; D024101:Mitochondrial Proteins; D011500:Protein Synthesis Inhibitors; D017382:Reactive Oxygen Species; C091648:TUFM protein, human; D002701:Chloramphenicol; D010444:Peptide Elongation Factor Tu