Molecular alterations of cells resistant to platinum drugs: Role of PKCα

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• 作者：Sabina C. Righetti ; Paola Perego ; Nives Carenini ; Elisabetta Corna ; Laura Dal Bo ; Sabrina Cedrola ; Caterina A.M. La Porta and Franco Zunino
• 关键词：Cisplatin ; Platinum drug ; Resistance ; Protein kinase C
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2006
• 出版时间：January 2006
• 年：2006
• 卷：1763
• 期：1
• 页码：93-100
• 全文大小：313 K

文摘

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 PKCα down-regulation. To explore the role of PKCα in cellular sensitivity to platinum compounds, resistant cells were transfected with a PKCα-containing vector. PKCα-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 PKCα 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 PKCα 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 PKCα as a determinant of the resistance status.