구강편평세포암종에서 상피세포 성장인자수용체의 Tyrosin 인산화 억제제에의한 P27KIP1, P21CIP1/WAF1 과 Cyclin D1의 발현이 세포성장에 미치는 영향 Critical Role of P27KIP1, P21CIP1/WAF1 and Cyclin D1 in the Antiproliferative Effect of Tyrosine Kinase Inhibitor(ZD1839) for Epidermal Growth Factor Receptor in the Human Oral Squamous Cell Carcinoma
pp.183-192
It is well known that the imbalance between epithelial cell growth and inhibitor factors may cause human epithelial cancer. Over-expression of the epidermal growth factor receptor(EGFR) has been implicated in the development of oral squamous cell carcinoma. ZD1839 inhibits selectively the EGFR tyrosine kinase activity and is clinically used for cancer patients. However the mechanisms by which it exerts its anti-tumor activity remains unclear. This study attempted to determine the mechanisms underlying the effects of ZD1839 on the cellular level and to characterize the effects of ZD1839 with regard to human oral squamous cell carcinoma(OSCC) cell growth. The YD-10B and YD-38 cell lines established from OSCC in the department of Oral Pathology, Yonsei University College of Dentistry and ZD1839(Iressa) were used for this study. The inhibition of cell proliferation induced by ZD1839 was reversible and the lowest dose of ZD1839 that produced statistically significant growth inhibition in YD cell lines were 0.1 μM. The delay in cell cycle progression was induced by 0.1 μM of ZD1839 treatment after 24 hr. This reduction in cell proliferation and cell cycle delay were associated with up-regulation of the cyclin dependent kinase inhibitor(CDKI), P21CIP1/WAF1 and P27KIP1. Reduced expression of cyclin D1 was also observed after treatment with ZD 1839 to YD-38 cells but not to YD-38. The present results suggest that the antiproliferative effects of ZD1839, in vitro was associated with degradation of cyclin D1, which may be used as a possible indicator of a high cell sensitivity to ZD1839.
II. MATERIALS AND METHODS
1. Cell Culture
2. Treatment with ZD1839
3. Cell Viability Assay
4. Cell Cycle Analysis
5. Western Blot Analysis
6. Statistical Analysis
III. RESULTS
1. Cytostatic effects of ZD1839 do not correlatewith EGFR Expression in Human OSCC
2. ZD1839 Induces Growth Inhibition throughG1 Cell Cycle Arrest
3. ZD1839 Treatment Upregulates CDK Inhibitors,p27KIP1 and p21CIP1/WAF1 and Downreglates cyclin D1
IV. DISCUSSION
V. REFERENCES