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Erlotinib, an Effective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces p27^KIP1 Up-Regulation and Nuclear Translocation in Association with Cell Growth Inhibition and G₁/S Phase Arrest in Human Non-Small-Cell Lung Cancer Cell Lines

Departments of Oncology (Y.H.L., T.L., M.H., R.P.-S.) and Molecular Genetics (Z.Y., T.K.W.), Albert Einstein College of Medicine, Bronx, New York

Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been shown to have potent antitumor effects against human non-small-cell lung cancer (NSCLC) cell growth; however, the mechanism of such an effect is not elucidated. Here, we demonstrate that erlotinib-induced cell growth inhibition in EGFR high-expressing human H322 NSCLC cells was accompanied by G₁/S phase arrest, which was largely caused by a decrease in expression of G₁/S-related cyclins, suppression of activities of cyclin-dependent kinase (CDK) 2 and CDK4, induction of CDK inhibitor p27^KIP1, and retinoblastoma hypophosphorylation. To further understand the role of p27^KIP1 in G₁/S arrest and cell growth inhibition by erlotinib, we determined its effect on the expression of p27^KIP1 at transcriptional and posttranscriptional levels. Studies using real-time reverse transcription-polymerase chain reaction analysis and p27 promoter-driven luciferase reporter showed that erlotinib treatment resulted in the promotion of p27 gene transcription. In addition, erlotinib treatment led to an increase in p27^KIP1 half-life by inhibiting p27^KIP1 phosphorylation at Thr187 and by down-regulating Skp2 expression. Furthermore, immunofluorescence staining and cell fractionation showed that erlotinib treatment led to p27^KIP1 translocation to the nucleus. Knockdown of p27^KIP1 expression with p27^KIP1 small interfering RNA significantly abrogated erlotinib-induced G₁ phase arrest and cell growth inhibition, suggesting that induction of p27^KIP1 is required for G₁ arrest and cell growth inhibition by erlotinib. It is noteworthy that we found that G₁ arrest and p27^KIP1 up-regulation by erlotinib occurred in the tested sensitive cell lines but to a lesser extent in the resistant cell lines. Taken together, these results suggest that erlotinib inhibits human NSCLC cell growth predominantly by inducing p27^KIP1 expression and by suppressing cell-cycle events involved in the G₁/S transition.

Address correspondence to: Dr. Roman Perez-Soler, Department of Oncology, Montefiore Medical Center, 111 East 210^th Street, Hofheimer 100, Bronx, New York 10467. E-mail: rperezso{at}montefiore.org

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