The Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor ZD1839 (Iressa) Suppresses Proliferation and Invasion of Human Oral Squamous Carcinoma Cells via p53 Independent and MMP, uPAR Dependent Mechanism

摘要

Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion and dissemination to cervical lymph nodes. Overexpression of the epidermal growth factor receptor (EGFR) and high levels of certain matrix metalloproteinases (MMPs) have been implicated in the development of squamous cell carcinoma of oral cancer. ZD1839 (Iressa) is a quinazoline derivative that selec tively inhibits the EGFR tyrosine kinase activity and is clinically used for cancer patients. This article attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level, and to character ize the effects of ZD1839 with regard to human OSCC cell growth and invasion/migration. The YD-10B cells represent a highly invasive human OSCC cell line, which has a frame shift p53 mutation. ZD1839 inhib ited the growth of the cell line in a time- and dose-dependent manner. Cell cycle kinetic analysis demonstrated that ZD1839 induces a delay in cell cycle progression and a G1 arrest. This induction of a G1 cell cycle arrest was associated with the upregulation of cyclin-dependent kinase inhibitors (CDKI) p27~(KIP1) and p21~(CIP1/WAF1). The upregulation of CDKI in ZD1839 treated cell lines may be mediated by a p53-independent and hnRNPC1/C2-dependent pathway. In addition, 100 nM ZD1839 demon strated that both MMP-2 and MMP-9 enzyme activity were decreased by ～25-30%. Reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that ZD1839 downregulated the uPAR mRNA level. These results might be associated with the reduction of MMP-2 and MMP-9 activities.