The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non-small cell lung cancer cells.
Celecoxib (Celebrex) is a cyclooxygenase-2 (COX-2) selective inhibitor and gefitinib (Iressa(R), ZD1839) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor for human non-small cell lung cancer (NSCLC). The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated. The Rad51 protein is essential for homologous recombination repair, and is overexpressed in chemo- or radioresistant carcinomas. In this study, we characterize the role of celecoxib in the cytotoxicity, ERK1/2 activation and Rad51 expression affected by gefitinib in NSCLC cells. We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells. Treatment with celecoxib alone has no effect on the ERK1/2 activation, Rad51 mRNA and protein levels, however, combined treatment with gefitinib results in a significant reduction of phospho-ERK1/2 and Rad51 protein levels, and triggers the degradation of Rad51 via a 26S proteasome-dependent pathway. Expression of constitutively active MKK1/2 vectors (MKK1/2-CA) significantly rescues the decreased ERK1/2 activity, and restores Rad51 protein levels and cell survival under co-treatment with gefitinib and celecoxib. Furthermore, blocking ERK1/2 activation by U0126 (MKK1/2 inhibitor) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib.
Ko
Jen-Chung
JC
Department of Internal Medicine, Hsinchu Hospital, Department of Health, The Executive Yuan, Taiwan.
Wang
Lyu-Han
LH
Jhan
Jhih-Yuan
JY
Ciou
Shih-Ci
SC
Hong
Jhao-Hao
JH
Lin
Szu-Ting
ST
Lin
Yun-Wei
YW
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D000077156:Gefitinib; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051135:Rad51 Recombinase / Q000096:biosynthesis* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D000068579:Celecoxib; D000077156:Gefitinib