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

ABSTRACT: The atypical protein kinase C (PKC) isoform zeta (PKC?) 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? in this event. PKC? 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? and induces resistance to apoptotic agents. Accordingly, chemoresistant cells show accumulation of PKC? within the nucleus, and a nuclear-targeted PKC? transfected in tumor cells decreases sensitivity to apoptosis. We thus developed a novel recombinant protein capable of selectively inhibiting the nuclear fraction of PKC? that restored the susceptibility to apoptosis in cells in which PKC? was enriched in the nuclear fraction, including chemoresistant cells. These findings establish the importance of PKC? as a possible target to increase the effectiveness of anticancer therapies and highlight potential sites of intervention.

SUBMITTER: Rimessi A 

PROVIDER: S-EPMC3323800 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature