PKCη is an anti-apoptotic kinase that predicts poor prognosis in breast and lung cancer.

The successful treatment of cancer in a disseminated stage using chemotherapy is limited by the occurrence of drug resistance, often mediated by anti-apoptotic mechanisms. Thus the challenge is to pinpoint the underlying key factors and to develop therapies for their direct targeting. Protein kinase C (PKC) enzymes are promising candidates, as some PKCs were shown to be involved in regulation of apoptosis. Our studies and others have shown that PKCη is an anti-apoptotic kinase, able to confer protection on tumour cells against stress and chemotherapy. We have demonstrated that PKCη shuttles between the cytoplasm and the nucleus and that upon DNA damage is tethered at the nuclear membrane. The C1b domain mediates translocation of PKCη to the nuclear envelope and, similar to the full-length protein, could also confer protection against cell death. Furthermore, its localization in cell and nuclear membranes in breast cancer biopsies of neoadjuvant-treated breast cancer patients was an indicator for poor survival and a predictor for the effectiveness of treatment. PKCη is also a novel biomarker for poor prognosis in non-small-cell lung cancer (NSCLC). Thus PKCη presents a potential target for therapy where inhibition of its activity and/or translocation to membranes could interfere with the resistance to chemotherapy.

DNA damage targets PKCη to the nuclear membrane via its C1b domain.

Translocation to cellular membranes is one of the hallmarks of PKC activation, occurring as a result of the generation of lipid secondary messengers in target membrane compartments. The activation-induced translocation of PKCs and binding to membranes is largely directed by their regulatory domains. We have previously reported that PKCη, a member of the novel subfamily and an epithelial specific isoform, is localized at the cytoplasm and ER/Golgi and is translocated to the plasma membrane and the nuclear envelope upon short-term activation by PMA. Here we show that PKCη is shuttling between the cytoplasm and the nucleus and that upon etoposide induced DNA damage is tethered at the nuclear envelope. Although PKCη expression and its phosphorylation on the hydrophobic motif (Ser675) are increased by etoposide, this phosphorylation is not required for its accumulation at the nuclear envelope. Moreover, we demonstrate that the C1b domain is sufficient for translocation to the nuclear envelope. We further show that, similar to full-length PKCη, the C1b domain could also confer protection against etoposide-induced cell death. Our studies demonstrate translocation of PKCη to the nuclear envelope, and suggest that its spatial regulation could be important for its cellular functions including effects on cell death.

PKCη is a novel prognostic marker in non-small cell lung cancer.

BACKGROUND: Novel biomarkers which may serve as therapeutic targets are essential for lung cancer treatment. Here we investigated the prognostic significance of protein kinase Cη (PKCη), a cell cycle regulator involved in tumorigenesis and chemotherapy resistance, in patients diagnosed with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Sixty-three chemotherapy-naïve patients were examined for PKCη by immunohistochemistry and divided into PKCη H-Score tertiles (low, intermediate and high). Time until event (relapse or mortality) within one year was determined using Cochran-Armitage test and Cox proportional hazards regression model. RESULTS: The distribution of patients according to clinical stage 1-4 was: 27%, 5%, 26% and 42%, respectively. PKCη overexpression was associated with advanced stage (p=0.03) and the risk for an event (p=0.045). Patients of the lowest tertile were less likely to experience an event. CONCLUSION: PKCη is a novel prognostic marker in NSCLC that may predict poor prognosis. The use of PKCη-specific inhibitors in NSCLC may prove valuable.