Glutathione transferase omega 1-1 (GSTO1-1) plays an anti-apoptotic role in cell resistance to cisplatin toxicity.
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.
Piaggi
Simona
S
Department of Experimental Pathology, University of Pisa, Via Roma 55, 56126 Pisa, Italy.
Raggi
Chiara
C
Corti
Alessandro
A
Pitzalis
Emanuela
E
Mascherpa
Marco C
MC
Saviozzi
Michela
M
Pompella
Alfonso
A
Casini
Alessandro F
AF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000494:pharmacology*; D020552:Comet Assay; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005978:Glutathione / Q000032:analysis; D005982:Glutathione Transferase / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014162:Transfection
D000970:Antineoplastic Agents; C490476:GSTO1 protein, human; D005982:Glutathione Transferase; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048055:Mitogen-Activated Protein Kinase 8; D005978:Glutathione; D002945:Cisplatin