BIM, a key proapoptotic member of the BCL-2 family of proteins, is essential for apoptosis triggered by tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR). However, the precise molecular mechanism by which EGFR-TKIs induce BIM expression has remained unclear. A previous study of ours showed that the activetion of c-Jun NH2-terminal kinase (JNK) is critical for the TKI-induced apoptosis in PC-9 cells, a gefitinib-sensitive human NSCLC cell line. In this study, we therefore examined the effect of JNK activation on BIM expression and further investigated the mechanism responsible for TKI-induced apoptosis in PC-9 cells. Northern blotting analysis revealed that the TKI AG1478 induced a substantial increase in the level of BIM mRNA. However, this TKI-induced increase was not observed in dominant-negative JNK overexpressing cell line J12A5 or in the TKI-resistant cell line HP-5R, in which JNK is not activated in response to AG1478. Therefore, JNK activation was correlated with the up-regulation of BIM expression. BIM is known to be a downstream target of forkhead box protein O (FOXO) transcription factors. Immunoblot analysis indicated that the levels of FOXO1, FOXO3a, and FOXO4 transcription factors increased after AG1478 treatment of PC-9 cells but that they were not increased in either J12A5 or HP-5R cells, indicating that FOXO was increased in PC-9 cells through JNK activation. FOXO1 knockdown in PC-9 cells decreased EGFR-TKI-induced BIM expression and apoptosis. These findings provide evidence that JNK activation and subsequent increased FOXO expression play a critical role in EGFR-TKI-induced BIM expression and apoptosis.
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