| Summary: | 碩士 === 國立嘉義大學 === 生化科技研究所 === 97 === Rad51 protein is essential for homologous recombination repair (HRR) for DNA damage, and is involved in the progress of carcinogenesis. Overexpression of Rad51 is associated with resistance to radiation or chemotherapy in tumor cells and poor prognosis. Overexpression of cyclooxygenase-2 (COX-2) has been characterized in several malignancies, including lung cancer. Previous studies have demonstrated that COX-2 inhibitors are effective chemopreventive agents to reduce the risks of lung cancer. Celecoxib (Celebrex®) is a selective cyclooxygenase-2 (COX-2) inhibitor and gefitinib (Iressa®, ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for human non-small cell lung cancer (NSCLC). The role of Rad51 in regulating the response to EGFR-TKIs and COX-2 inhibitor in different cell types of human lung cancer still remains to be determined. In addition, the molecular mechanism of the additive cytotoxic effect of celecoxib in gefitinib- treated human lung cancer cells also needs to be investigated. In this study, we will define the role of celecoxib in cell survival, ERK1/2 activation and Rad51 expression affected by gefitinib in human NSCLC cells. The results show that celecoxib can enhance the cytotoxic effect of gefitinib in human lung cancer cells. Treatment with celecoxib alone has no effect on the ERK1/2 activation, Rad51 mRNA and protein levels. However, celecoxib in combination with gefitinib could additively decrease phospho-ERK1/2 and Rad51 protein levels, and trigger Rad51 degradation via the 26S proteasome-dependent pathway. Our results also imply that MEK1/2-ERK1/2 is the upstream signal for maintaining the Rad51 protein levels. In addition, suppression of Rad51 expression by transfection with small interfering RNA of Rad51 can enhance celecoxib-induced cytotoxicity. In conclusion, knocking down Rad51 protein expression may be a novel and better therapeutic modality for lung cancer treated with EGFR and COX-2 inhibitors.
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