TY - JOUR T1 - RETRACTION: Erlotinib, an Effective Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, Induces p27<em><sup>KIP1</sup></em> Up-Regulation and Nuclear Translocation in Association with Cell Growth Inhibition and G<sub>1</sub>/S Phase Arrest in Human Non-Small-Cell Lung Cancer Cell Lines JF - Molecular Pharmacology JO - Mol Pharmacol SP - 248 LP - 258 DO - 10.1124/mol.107.034827 VL - 72 IS - 2 AU - Yi-He Ling AU - Tianhong Li AU - Ziqiang Yuan AU - Missak Haigentz, Jr. AU - Thomas K. Weber AU - Roman Perez-Soler Y1 - 2007/08/01 UR - http://molpharm.aspetjournals.org/content/72/2/248.abstract N2 - 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 p27KIP1, and retinoblastoma hypophosphorylation. To further understand the role of p27KIP1 in G1/S arrest and cell growth inhibition by erlotinib, we determined its effect on the expression of p27KIP1 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 p27KIP1 half-life by inhibiting p27KIP1 phosphorylation at Thr187 and by down-regulating Skp2 expression. Furthermore, immunofluorescence staining and cell fractionation showed that erlotinib treatment led to p27KIP1 translocation to the nucleus. Knockdown of p27KIP1 expression with p27KIP1 small interfering RNA significantly abrogated erlotinib-induced G1 phase arrest and cell growth inhibition, suggesting that induction of p27KIP1 is required for G1 arrest and cell growth inhibition by erlotinib. It is noteworthy that we found that G1 arrest and p27KIP1 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 p27KIP1 expression and by suppressing cell-cycle events involved in the G1/S transition. ER -