An increment of thioredoxin-1 (TRX) is observed in many human primary cancers and appears to contribute to an increase of cell growth and a resistance to chemotherapy. On the contrary, when TRX was overexpressed in the HT-1080 fibrosarcoma cells, the cell growth was retarded and chromosomal polyploidy and cellular senescence were induced. TRX-overexpression made HT-1080 cells resistant to an oxidative stress caused by H 2 O 2 or paraquat. But these cells were significantly sensitive to ionizing radiation, showing an abrogation of the G 2 checkpoint. Their DNA contents were twice of the controls and they expressed typical senescence markers. Their expression levels of p53 and cyclin-dependent kinase inhibitors (CDKI) were about 2-3-fold higher than the control. Nevertheless, cyclin D1 and D3, which are negatively regulated by CDKIs, were also increased. Overall, in HT-1080 cells the TRX-overexpression created a state of cellular senescence caused by a simultaneous stimulation of the mitogen-activated pathways and an inhibition of the cyclin-dependent kinases, which is known as a hypermitogenic arrest.
Recent studies indicate that reactive oxygen species, such as H2O2, can be generated by anti-cancer drugs, can damage cells, and then induce apoptotic cell death. In this study, we reported whether polyamines were capable of affecting apoptotic cell death triggered by H2O2 in leukemia cells or not. Alpha-difluoromethylornithine treatment (DFMO, 3 mmol/L, 48 h), which depletes intracellular putrescine by inhibiting ornithine decarboxylase, reduced H2O2-induced cell death in the HL-60 leukemia cells. Cytotoxicity caused by H2O2 in putrescine-depleted cells was 50% lower than that in the control cells, as determined by propidium iodide, the annexin V and DNA fragmentation assays. Following putrescine (1 mmol/L) supplement, cell death induction caused by H2O2 was restored to a similar level as the DFMO-untreated control cells. It seems that this partly resulted from the intralysosomal iron-dependent oxidation of the cells because DFMO did not significantly affect the increment of enzymes related to oxidative-stress resistance. Putrescine depletion by DFMO treatment reduced the cellular iron uptake of the cells by about 70%. In parallel to the reduction of iron uptake, lysosomal damage (assayed by acridine orange relocalization or uptake test) in the DFMO-treated cells was far less than that in the control cells. Moreover, putrescine supplement also restored the iron uptake to the control cell levels. Pre-incubation with desferrioxamine (DFO), which chelates iron and forms a non-reactive Fe-DFO complex that is localized in the lysosomal compartment, inhibited H2O2-induced cell death. This work suggests that polyamines may play a critical role in apoptotic cell death triggered by H2O2 via the regulation of the iron-dependent instability of the lysosome.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.