The selective inhibition of nuclear PKC zeta restores the effectiveness of chemotherapeutic agents in chemoresistant cells

The atypical protein kinase C (PKC) isoform zeta (PKC zeta) has been implicated in the intracellular transduction of mitogenic and apoptotic signals by acting on different signaling pathways. The key role of these processes in tumorigenesis suggests a possible involvement of PKC zeta in this event. PKC zeta is activated by cytotoxic treatments, inhibits apoptotic cell death and reduces the sensitivity of cancer cells to chemotherapeutic agents. Here, using pharmacological and DNA recombinant approaches, we show that oxidative stress triggers nuclear translocation of PKC zeta and induces resistance to apoptotic agents. Accordingly, chemoresistant cells show accumulation of PKC zeta within the nucleus, and a nuclear-targeted PKC zeta transfected in tumor cells decreases sensitivity to apoptosis. We thus developed a novel recombinant protein capable of selectively inhibiting the nuclear fraction of PKC zeta that restored the susceptibility to apoptosis in cells in which PKC zeta was enriched in the nuclear fraction, including chemoresistant cells. These findings establish the importance of PKC zeta as a possible target to increase the effectiveness of anticancer therapies and highlight potential sites of intervention.