Lapatinib induces p27Kip1-dependent G1 arrest through both transcriptional and post-translational mechanisms

Lin Tang, Yucai Wang, Anders Strom, Jan Ake Gustafsson, Xiaoxiang Guan

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Lapatinib, a dual EGFR/HER 2 tyrosine kinase inhibitor, has been shown to have potent antitumor effects against human breast cancer. Recent studies have shown that lapatinib upregulates p27Kip1 (here after referred to as p27) expression and induces G1 cell cycle arrest in various types of cancer cells. However, the regulation of p27 in lapatinib-induced cell cycle arrest is not well studied. Here we demonstrate that lapatinib-induced cell growth inhibition and G1 cell cycle arrest in HER 2-overexpressing human breast cancer cells were dependent on p27. We also show that lapatinib-induced upregulation of p27 expression was mediated through both transcriptional and post-translational mechanisms. On the one hand, lapatinib treatment led to increased FOXO 3a expression and enhanced p27 transcription. On the other hand, lapatinib treatment resulted in increased DYR K1B expression, which correlated with increased p27 phosphorylation at Ser10 and decreased p27 degradation. Interestingly, we found that ER β1 but not ER β2 expression also upregulated p27 and enhanced lapatinib-induced cell proliferation inhibition and G1 cell cycle arrest in HER 2-overexpressing breast cancer cells. Taken together, our results suggest that lapatinib induces p27 expression via both transcriptional and post-translational upregulations, leading to cell cycle arrest and cell proliferation inhibition, and that its effect on breast cancer cells may be modified by ER expression status.

Original languageEnglish (US)
Pages (from-to)2665-2674
Number of pages10
JournalCell Cycle
Volume12
Issue number16
DOIs
StatePublished - Aug 15 2013

Keywords

  • ERβ1
  • ERβ2
  • G1 arrest
  • Lapatinib
  • P27

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Developmental Biology

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