Cisplatin resistance is associated with deregulation in protein kinase C-δ

Proteolytic activation of protein kinase C (PKC)-δ has been associated with cell death induced by the DNA damaging agent cisplatin. In the present study, we have examined if PKCδ is affected when cells acquire resistance to cisplatin. The level of PKCδ was elevated in cisplatin-resistant HeLa (HeLa/CP) cells compared to parental HeLa cells. Prolonged cellular exposure to the PKC activator phorbol-12,13-dibutyrate (PDBu), caused downregulation of PKCδ in HeLa cells but not in HeLa/CP cells. Treatment of HeLa cells with PDBu resulted in the translocation of PKCδ from the cytosol to the membrane but it failed to induce PKCδ translocation in HeLa/CP cells. PDBu, however, induced translocation and downregulation of PKCα in both HeLa and HeLa/CP cells. The ability of PDBu to enhance cisplatin-induced cell death was attenuated in cisplatin-resistant HeLa cells. Thus, a deregulation in PKCδ was associated with reduced cellular sensitivity to cisplatin.