The role of repair protein Rad51 in synergistic cytotoxicity and mutagenicity induced by epidermal growth factor receptor inhibitor (Gefitinib, IressaR) and benzo[a]pyrene in human lung cancer |
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Authors: | Ko Jen-Chung Hong Jhao-Hao Wang Lyu-Han Lin Yun-Wei |
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Institution: | Department of Internal Medicine, Hsinchu Hospital, Taiwan. |
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Abstract: | Rad51 protein is essential for homologous recombination repair of DNA damage, and is over-expressed in chemo- or radioresistant carcinomas. The polycyclic hydrocarbon carcinogen benzoa]pyrene (Ba]P) affects MAPKs transduction pathways. Gefitinib (IressaR, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that blocks growth factor-mediated cell proliferation and ERK1/2 activation. We hypothesized that gefitinib enhances Ba]P-mediated cytotoxicity by decreasing ERK1/2 activation. Exposure of human lung cancer cells to gefitinib decreased Ba]P-elicited ERK1/2 activation and induced Rad51 protein expression. Gefitinib and Ba]P co-treatment decreased Rad51 protein stability by triggering degradation via a 26S proteasome-dependent pathway. Expression of constitutive active MKK1/2 vectors (MKK1/2-CA) rescues the decreased ERK1/2 activity, and restores Rad51 protein level and stability under gefitinib and Ba]P co-treatment. Gefitinib enhances Ba]P-induced growth inhibition, cytotoxicity and mutagenicity. Co-treatment with gefitinib and Ba]P can further inhibit cell growth significantly after depletion of endogenous Rad51 by siRad51 RNA transfection. Enhancement of ERK1/2 activation by MKK1-CA expression decrease Ba]P- and gefitinib-induced cytotoxicity, and Ba]P-induced mutagenicity. Rad51 protein protects lung cancer cells from synergistic cytotoxic and mutagenic effects induced by gefitinib and Ba]P. Suppression of Rad51 protein expression may be a novel lung cancer therapeutic modality to overcome drug resistance to gefitinib. |
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Keywords: | B[a]P Benzo[a]pyrene MAPK mitogen-activated protein kinase ERK1/2 extracellular signal-regulated kinase-1/2 BPDE benzo[a]pyrene-7 8-diol-9 10-epoxide siRNA small interfering RNA ALLN N-acetyl-Leu-Leu-norleucinal |
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