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Carcinogenesis Advance Access originally published online on June 9, 2008
Carcinogenesis 2008 29(7):1448-1458; doi:10.1093/carcin/bgn130
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Involvement of Rad51 in cytotoxicity induced by epidermal growth factor receptor inhibitor (gefitinib, IressaR) and chemotherapeutic agents in human lung cancer cells

Jen-Chung Ko, Shih-Ci Ciou1, Chau-Ming Cheng1, Lyu-Han Wang1, Jhao-Hao Hong1, Ming-Yan Jheng1, Szu-Ting Ling1 and Yun-Wei Lin1,*

Department of Internal Medicine, Hsinchu Hospital, Department of Health, The Executive Yuan, Taiwan
1 Molecular Oncology Laboratory, Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan

* To whom correspondence should be addressed. Tel: +886 5 271 7770; Fax: +886 5 271 7780; Email: linyw{at}mail.ncyu.edu.tw

Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor (EGFR) 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 antitumor 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 messenger RNA (mRNA). However, gefitinib cotreatment 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 mitogen-activated protein kinase kinase 1/2 (MKK1/2-CA) increased Rad51 protein levels and protein stability in gefitinib and cisplatin or MMC cotreated cells. Moreover, the synergistic cytotoxic effects induced by gefitinib cotreatment with cisplatin or MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by si-Rad51 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.

Abbreviations: ALLN, N-acetyl-Leu-Leu-norleucinal; CFA, colony-forming ability; CI, combination index; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1/2; MAPK, mitogen-activated protein kinase; MKK1/2-CA, constitutively active form of mitogen-activated protein kinase kinase; MMC, mitomycin C; mRNA, messenger RNA; NSCLC, non-small-cell lung cancer; PTEN, phosphatase and tensin homolog deleted on chromosome 10; siRNA, small interfering RNA; TKI, tyrosine kinase inhibitor

Received January 17, 2008; revised April 30, 2008; accepted May 22, 2008.


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J.-C. Ko, S.-C. Ciou, J.-Y. Jhan, C.-M. Cheng, Y.-J. Su, S.-M. Chuang, S.-T. Lin, C.-C. Chang, and Y.-W. Lin
Roles of MKK1/2-ERK1/2 and Phosphoinositide 3-Kinase-AKT Signaling Pathways in Erlotinib-Induced Rad51 Suppression and Cytotoxicity in Human Non-Small Cell Lung Cancer Cells
Mol. Cancer Res., August 1, 2009; 7(8): 1378 - 1389.
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