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J. Bean, C. Brennan, J. Y. Shih, G. Riely, A. Viale, L. Wang, D. Chitale, N. Motoi, J. Szoke, S. Broderick, M. Balak, W. C. Chang, C. J. Yu, A. Gazdar, H. Pass, V. Rusch, W. Gerald, S. F. Huang, P. C. Yang, V. Miller, M. Ladanyi, C. H. Yang and W. Pao, “MET Amplification Occurs with or without T790M Mutations in EGFR Mutant Lung Tumors with Acquired Resistance to Gefitinib or Erlotinib,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 5, 2007, pp. 20932-20937.

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• TITLE: JNK-Mediated FOXO Expression Plays a Critical Role in EGFR Tyrosine Kinase Inhibitor-Induced BIM Expression and Apoptosis

  AUTHORS: Kenji Takeuchi, Anh Ho Viet, Katsumi Kawasaki, Kazuto Nishio, Fumiaki Ito

  KEYWORDS: EGFR-TKI; FOXO; BIM; JNK; NSCLC

  JOURNAL NAME: Journal of Cancer Therapy, Vol.3 No.4A, September 12, 2012

  ABSTRACT: 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.