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

• Published in: Carcinogenesis (New York) Vol. 29; no. 7; pp. 1448 - 1458
• Main Authors: Ko, Jen-Chung, Ciou, Shih-Ci, Cheng, Chau-Ming, Wang, Lyu-Han, Hong, Jhao-Hao, Jheng, Ming-Yan, Ling, Szu-Ting, Lin, Yun-Wei
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-07-2008; Oxford Publishing Limited (England)
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Non-Small-Cell Lung - drug therapy; Cisplatin - administration & dosage; Cisplatin - pharmacology; Drug Synergism; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; MAP Kinase Kinase 1 - biosynthesis; MAP Kinase Kinase 1 - genetics; MAP Kinase Kinase 1 - metabolism; MAP Kinase Signaling System; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Mitomycin - administration & dosage; Mitomycin - pharmacology; Phosphorylation; Pneumology; Proteasome Endopeptidase Complex - metabolism; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Quinazolines - administration & dosage; Quinazolines - pharmacology; Rad51 Recombinase - biosynthesis; Rad51 Recombinase - genetics; Rad51 Recombinase - physiology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Transfection; Tumors; Tumors of the respiratory system and mediastinum; Antineoplastic agent; Human; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Quinazoline derivatives; Transferases; Lung cancer; Enzyme inhibitor; Cytotoxicity; Malignant tumor; Bronchopulmonary; Epidermal growth factor receptor; Repair gene; Growth factor receptor; Bronchus disease; Gefitinib; Mechanism of action; Protein-tyrosine kinase; Tumor cell; Cancer
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgn130

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.