Development of resistance to platinum compounds may involve not only overexpression of defence mechanisms but also alterations in cellular response to the drug-induced genotoxic stress. To investigate the cellular bases of response to platinum compounds, we examined the profile of gene expression of ovarian carcinoma cells exhibiting sensitivity (A2780) or resistance (A2780/BBR3464) to platinum compounds. Using display PCR, we found that acquisition of resistance to the multinuclear platinum complex BBR3464 was associated with modulation of several transcripts, including up-regulation of the major substrate of protein kinase C (PKC), the myristoylated alanine-rich C kinase substrate (MARCKS). This feature was associated with PKC alpha down-regulation. To explore the role of PKC alpha in cellular sensitivity to platinum compounds, resistant cells were transfected with a PKC alpha-containing vector. PKC alpha-overexpressing resistant cells exhibited a decrease in sensitivity to cisplatin, whereas no significant change in sensitivity to BBR3464 was observed. A number of approaches designed to modulate the function or expression of PKC alpha support that the isoenzyme may play a role in determining resistance only to cisplatin but not to BBR3464, which is known to activate a different pathway of cell response. In conclusion, in spite of PKC alpha down-regulation in our model, its regulatory function was not apparently implicated in the development of resistance to platinum compounds and the present results do not support a general role of PKC alpha as a determinant of the resistance status.
|Titolo:||Molecular alterations of cells resistant to platinum drugs : role of PKCα|
|Autori interni:||LA PORTA, CATERINA (Penultimo)|
PEREGO, PAOLA (Secondo)
|Parole Chiave:||Cisplatin; Platinum drug; Protein kinase C; Resistance|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||gen-2006|
|Digital Object Identifier (DOI):||10.1016/j.bbamcr.2005.12.007|
|Appare nelle tipologie:||01 - Articolo su periodico|
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