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
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Di Gennaro, E
Barbarino, M
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Barbarino, M
Bruzzese, F
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Bruzzese, F
De Lorenzo, S
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
De Lorenzo, S
Caraglia, M
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Caraglia, M
Abbruzzese, A
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Abbruzzese, A
Avallone, A
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Avallone, A
Comella, P
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Comella, P
Caponigro, F
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Caponigro, F
Pepe, S
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Pepe, S
Budillon, A
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机构:Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
Budillon, A
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[1] Ist Nazl Tumori G Pascale, Dipartimento Oncol Sperimentale, I-80131 Naples, Italy
[2] Ist Nazl Tumori G Pascale, Dipartimento Oncol Med, I-80131 Naples, Italy
[3] Univ Naples Federico II, Dipartimento Endocrinol & Oncol Mol & Clin, Naples, Italy
[4] Univ Naples 2, Dipartimento Biochim & Biofis F Cedrangolo, Naples, Italy
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 p27(KIP1) and p21(CIP1/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 p27(KIP1) and p21(CIP1/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 p27(KIP1) or p21(CIP1/WAF1) antisense constructs. Overall, these results as well as the timing of the effect of ZD1839 on G1 arrest and p27(KIP1) and p21(CIP1/WAF1) upregulation, suggest a mechanistic connection between these events. (C) 2003 Wiley-Liss, Inc.