Am J Cancer Res 2011;1(7):823-833

Original Article
N-cadherin expression is a potential survival mechanism of gefitinib-resistant
lung cancer cells

Mai Yamauchi, Ikuyo Yoshino, Rui Yamaguchi, Teppei Shimamura, Masao Nagasaki, Seiya Imoto, Atsushi Niida, Fumiaki
Koizumi, Takashi Kohno, Jun Yokota, Satoru Miyano, Noriko Gotoh

Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Human Genome
Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Division of Genetics, National Cancer Center Research
Institute, Tokyo, Japan; Division of Genome Biology, Division of Multistep Carcinogenesis, National Cancer Center Research
Institute, Tokyo, Japan.

Received June 28, 2011; accepted July 16, 2011; Epub August 8, 2011; Published August 30, 2011

Abstract: Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer and is the most common and fatal cancer
worldwide. Specific tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR), such as gefitinib, have been effective
in some NSCLC patients and are being used in the clinical setting as pioneer molecularly targeted cancer drugs. However,
many patients have not responded to these drugs, and have acquired resistance after long-term treatment. To identify other
potential NSCLC molecular targets, we used DNA microarrays to examine gene expression profiles of gefitinib-resistant PC9/ZD
cells that are derived from gefitinib-sensitive PC9 cells and harbor a threonine to methionine mutation at codon 790 (T790M) in
EGFR, a known mechanism of acquired resistance to gefitinib. We found that N-cadherin expression was significantly
upregulated in PC9/ZD cells compared with PC9 cells. Inhibition of N-cadherin expression by siRNA or treatment with antibodies
against N-cadherin induced apoptosis of PC9/ZD cells in association with reduced phosphorylation of Akt and Bad, a
proapoptotic protein. Moreover, inhibition of Akt expression by siRNA or treatment with an inhibitor for phosphatidylinositol (PI)-3
kinase reduced survival of PC9/ZD cells. In addition, we found several N-cadherin-expressing lung cancer cells that showed
inherent resistance to gefitinib treatment and reduced survival owing to siRNA-induced inhibition of N-cadherin expression.
Thus, it appears that N-cadherin maintains the survival of the gefitinib-resistant lung cancer cells via the PI-3 kinase/Akt survival
pathway. From these results, we propose that N-cadherin signaling contributes, at least in part, to the survival mechanisms of
gefitinib-resistant NSCLC cells and that N-cadherin is a potential molecular target in the treatment of NSCLC. (AJCR0000074).

Keywords: NSCLC, EGFR, TKI, PC9, PI-3 kinase, Akt, microarray, gene expression profiling, Meta Gene profier

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Address all correspondence to:
Noriko Gotoh, MD, PhD
Associate Professor
Division of Systems Biomedical Technology, Institute of Medical Science,
University of Tokyo
4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
Tel.: +81 3 5449 5629; Fax: +81 3 5449 5425
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American Journal of Cancer Research
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