Journal
CARCINOGENESIS
Volume 31, Issue 5, Pages 804-811Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/bgq031
Keywords
-
Categories
Funding
- Italian Ministry for University and Research [prot. 20077S9A32_004]
- Istituto Toscano Tumori (Firenze, Italy)
Ask authors/readers for more resources
Several lines of evidence correlate the overexpression of glutathione S-transferase omega 1-1 (GSTO1-1) with the onset of drug resistance of cancer cells; however, no direct evidence is yet available. In order to investigate the mechanisms involved, stable transfection with GSTO1-1 complementary DNA was performed in HeLa cells, which spontaneously express very low levels of GSTO1-1. When transfected cells were seeded at low density, a sharp increase in GSTO1-1 expression was observed as compared with controls, along with an increased resistance against cisplatin cytotoxicity. When seeded at increasing densities, control untransfected cells also presented with an increase in GSTO1-1 expression, again accompanied by cisplatin resistance; the latter was significantly reduced after transfection with GSTO1-1 small interfering RNA. Cisplatin resistance of transfected cells was not accounted for by changes in the intracellular drug concentration nor in the amount of DNA cross-links or content of glutathione. Rather, transfected cells presented with a marked decrease of apoptosis as compared with controls, suggesting that GSTO1-1 overexpression may prevent cisplatin toxicity by interfering with the apoptotic process. Cisplatin treatment was in fact followed at early times (1-2 h) by activation of both Akt kinase and extracellular signal-regulated kinase (ERK)-1/2 in the transfected cells but not in controls. Conversely, in transfected cells, the strong activation of Jun N-terminal kinase (JNK)-1 induced by cisplatin at later times (10-20 h) was completely prevented. In conclusion, GSTO1-1 overexpression appears to be associated with activation of survival pathways (Akt and ERK1/2) and inhibition of apoptotic pathways (JNK1), as well as protection against cisplatin-induced apoptosis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available