被撤回的出版物: Erlotinib, an effective epidermal growth factor receptor tyrosine kinase inhibitor, induces p27KIP1 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in association with cell growth inhibition and G1/S phase arrest in human non-small-cell lung cancer cell lines (Retracted article. See vol. 88, pg. 390, 2015)

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 G(1)/S phase arrest, which was largely caused by a decrease in expression of G(1)/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 G(1)/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 G(1) phase arrest and cell growth inhibition, suggesting that induction of p27(KIP1) is required for G(1) arrest and cell growth inhibition by erlotinib. It is noteworthy that we found that G(1) 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 G(1)/S transition.