C-JUN NH2-TERMINAL KINASE REGULATION OF THE APOPTOTIC RESPONSE OF SMALL-CELL LUNG-CANCER CELLS TO ULTRAVIOLET-RADIATION

Exposure of cultured small cell lung cancer (SCLC) cells to UV radiati on induces apoptosis. We observed that the UV sensitivity of a panel o f SCLC lines and the activation of c-Jun NH2-terminal kinases (JNKs) b y UV in the individual SCLC lines, assessed by binding and phosphoryla tion of glutathione S-transferase (GST)-c-Jun fusion proteins, ranged widely. In fact, increased JNK activity in this assay was closely corr elated with decreased sensitivity to apoptosis following UV irradiatio n. Increased JNK activity was also detected in anti-JNK1 immune comple xes collected from UV-irradiated SCLC cells, although the level of act ivity was similar among the various SCLC lines and correlated poorly w ith UV sensitivity. Immunoblot analysis of JNK polypeptides that bound to GST c-Jun revealed at least two JNK polypeptides, one of which app eared only in extracts from UV-irradiated SCLC. To test the role of JN Ks in UV-induced apoptosis, nonphosphorylatable mutants of JNK1 or JNK 2 in which the phosphorylation site Thr-Pro-Tyr is changed to Ala-Pro- Phe (JNK-APF) and are predicted to behave as competitive inhibitors we re stably expressed in SCLC. Expression of JNK1-APF or JNK2-APF signif icantly reduced UV-stimulated JNK activity. However, JNK1-APF markedly increased the resistance of the cells to UV-induced apoptosis, while JNK2-APF did not influence SCLC sensitivity to UV. The findings sugges t that UV-stimulated JNK1 activation promotes UV-induced SCLC apoptosi s, while a JNK isoform that is variably activated among the SCLC lines may signal a UV-protective response. We hypothesize that integration of distinct JNK activities dictates the relative responsiveness of SCL C to UV and ionizing radiation.