Role of MKP-1 and NFkB on survival of non-small cell lung carcinoma cells to cisplatin

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Non-small cell lung cancer (NSCLC) represents the most frequent and therapy-resistant subclass of lung cancer. In this situation improving apoptosis represents a logical way to advance in treatment of this tumor. Cisplatin is a commonly used agent in NSCLC treatment that induces activation of both JNK and NFkB signaling pathways. By analyzing surgical samples of NSCLC we have found that expresion of MKP1, a negative regulator of JNK, showed a strong nuclear staining for tumor cells while in normal bronchial epithelia MKP1 was localized in cytoplasm as well as in nuclei. We have used two NSCLC derived cell lines, H460 and H1299, that differentially expressed MKP1 and NFkB activity, in order to study the role of both pathways in cisplatin induced cell death. MKP1 is constitutively expressed in H460 cells. By expressing a siRNA vector for MKP1 we found that in H460 MKP1/siRNA cells, cisplatin induces more efficiently activation of JNK and p38 than in parental cells and that correlated with an increase in 10-fold sensitivity to cisplatin. By contrast to H460, no differences in survival were observed in H1299 expressing the MKP1siRNA. H460MKP1siRNA cells grow both slower in nu-/nu- mice and also show more susceptibility to cisplatin than parental cells, hence resulting in an impaired growth of the tumor in mice. H1299 cells showed constitutive NFkB activity but no MKP1expression and in these cells, BAY11-7082 treatment enhance the anti-tumor activity of cisplatin while only weakly affected the response of H460 cells. Altogether, the results showed that inhibition of MKP1 expression contributes to a slower growth of cells in mice and also to an increase of cisplatin induced cell death in NSCLC. On the other hand constitutive NFkB activity can also acts as a survival pathway to cisplatin and its selective inhibition contributes to cell death in these cells. Altogether, the results suggest that a potent chemo-sensitization to cisplatin in NSCLC can be obtained by a selective inhibition of MKP1 or NFkB activities when selecting the tumors with the appropriate molecular studies.