Abstract
Receptor-mediated overexpression of H2O2-generating peroxisomal fatty acyl-CoA oxidase (AOX) has been implicated in peroxisome proliferator-induced hepatocarcinogenesis. To investigate the role of rat AOX generated H2O2 in transformation, we overexpressed this enzyme in a non-tumorigenic mouse fibroblast cell line (LM tk-) under control of mouse urinary protein promoter. The clones overexpressing rat peroxisomal AOX, when exposed to a fatty acid substrate (100 microM linoleic acid) for 6 to 96 h, demonstrated > 10-fold increase of intracellular H2O2. This increase in H2O2 concentration was associated with increased apoptosis as evidenced by DNA fragmentation, in situ terminal deoxynucleotide transferase dUTP nick end-labeling (TUNEL). These cell lines stably expressing AOX formed colonies in soft agar in proportion to the duration (1-7 weeks) of exposure to a fatty acid substrate (100 microM linoleic acid, erucic acid or nervonic acid) and these transformants developed into fibrosarcomas when injected in athymic nude mice. These results suggest that H2O2 generated by AOX overexpression in immortalized fibroblasts leads to apoptosis, and the extent and duration of H2O2 and possibly other DNA damaging reactive oxygen species generated by the overexpression of peroxisomal AOX can influence apoptosis and neoplastic transformation.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.