Carcinogenesis Advance Access published online on June 9, 2008
Carcinogenesis, doi:10.1093/carcin/bgn130
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Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (Gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells
1 Department of Internal Medicine, Hsinchu Hospital, Department of Health, The Executive Yuan, Taiwan
2 Molecular Oncology Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
* Address correspondence to: Yun-Wei Lin, Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan, Tel: 886-5-271-7770; Fax: 886-5-271-7780; E-mail: linyw{at}mail.ncyu.edu.tw
Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) signaling activation. Rad51 is an essential component of the homologous recombination repair pathway. High level of Rad51 expression has been reported in chemo- or radioresistant carcinomas. We hypothesized that gefitinib may enhance the effects of the alkylating agent cisplatin or the anti-tumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing ERK1/2 activation and Rad51 expression. Exposure of human non-small lung cancer cells to gefitinib decreased cisplatin or MMC-elicited ERK1/2 activation and Rad51 protein induction. Neither cisplatin nor MMC treatment affected Rad51 mRNA. However, gefitinib co-treatment with cisplatin or MMC significantly decreased Rad51 mRNA levels. In addition, gefitinib decreased cisplatin or MMC-elicited Rad51 protein levels by increasing Rad51 protein instability. Enhancement of ERK1/2 signaling by constitutively active MKK1/2 (MKK1/2-CA) increased Rad51 protein levels and protein stability in gefitinib and cisplatin or MMC co-treated cells. Moreover, the synergistic cytotoxic effects induced by gefitinib co-treatment with cisplatin or MMC was remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by siRad51 RNA transfection significantly enhanced lung cancer cell death upon treatment with cisplatin or MMC. We conclude that Rad51 protein protects lung cancer cells from synergistic cytotoxic effects induced by gefitinib and chemotherapeutic agents. Suppression of Rad51 expression may be a novel lung cancer therapeutic modality to overcome drug resistance to EGFR inhibitors and chemotherapeutic agents.
Key Words: Rad51 • gefitinib • cisplatin • mitomycin C • ERK1/2 • cytotoxicity
Received January 17, 2008; revised April 30, 2008; accepted May 22, 2008.
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