Critical role of both p27KIP1 and p21CIP1/WAF1 in the antiproliferative effect of ZD1839 ('Iressa'), an epidermal growth factor receptor tyrosine kinase inhibitor, in head and neck squamous carcinoma cells

Elena Di Gennaro, Marcella Barbarino, Francesca Bruzzese, Sonya De Lorenzo, Michele Caraglia, Alberto Abbruzzese, Antonio Avallone, Pasquale Comella, Francesco Caponigro, Stefano Pepe, Alfredo Budillon

Research output: Contribution to journalArticle

Abstract

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of squamous-cell carcinomas of head and neck (SCCHN). ZD1839 ('Iressa') is an orally active, selective EGFR-TKI (EGFR-tyrosine kinase inhibitor) that blocks signal transduction pathways implicated in proliferation and survival of cancer cells, and other host-dependent processes promoting cancer growth. We have demonstrated that ZD1839 induces growth arrest in SCCHN cell lines by inhibiting EGFR-mediated signaling. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest together with a partial G2/M block; this was associated with increased expression of both p27KIP1 and p21CIP1/WAF1 cyclin-dependent kinase (CDK) inhibitors. The activity of CDK2, the main target of CIP/KIP CDK inhibitors, was reduced in a dose-dependent fashion after 24 h of ZD1839 treatment and this effect correlated to the increased amount of p27KIP1 and p21CIP1/WAF1 proteins associated with CDK2-cyclin-E and CDK2-cyclin-A complexes. In addition, ZD1839-induced growth inhibition was significantly reduced in cell transfectants expressing p27KIP1 of p21CIP1/WAF1 antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27KIP1 and p21CIP1/WAF1 upregulation, suggest a mechanistic connection between these events.

Original languageEnglish
Pages (from-to)139-150
Number of pages12
JournalJournal of Cellular Physiology
Volume195
Issue number1
DOIs
Publication statusPublished - Apr 1 2003

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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