Role of repair protein Rad51 in regulating the response to gefitinib in human non-small cell lung cancer cells.

Full Abstract

Gefitinib (Iressa, ZD1839) is a selective epidermal growth factor receptor tyrosine kinase inhibitor that can block growth factor-mediated cell proliferation and extracellular signal-regulated kinases 1/2 (ERK1/2) activation. High-level Rad51 expression has been reported in chemoresistant or radioresistant carcinomas. In this study, we examined the role of Rad51 in regulating the response to gefitinib among different human lung cancer cell lines. The H520 line (human squamous cell carcinoma) was less sensitive to gefitinib compared with the H1650 (human adenocarcinoma) or A549 (human bronchioloalveolar carcinoma) lines. In H1650 and A549 cells but not in H520 cells, gefitinib decreased cellular levels of phospho-ERK1/2 and Rad51 protein and message levels. Moreover, gefitinib decreased Rad51 protein levels by enhancing Rad51 protein instability through 26S proteasome-mediated degradation. Inhibition of endogenous Rad51 levels by si-Rad51 RNA transfection significantly enhanced gefitinib-induced cytotoxicity. In contrast, transfection with constitutively active MKK1 vector could restore both Rad51 protein levels and cell survival inhibited by gefitinib. The MKK1/2-ERK1/2 signaling pathway constitutes the upstream signaling for maintaining Rad51 message and protein levels. Rad51 protein can protect lung cancer cells from cytotoxic effects induced by gefitinib. Suppression of Rad51 may be a novel lung cancer therapeutic modality to overcome drug resistance to gefitinib.

Author information

Author/s: Ko, Jen-Chung (JC); Hong, Jhao-Hao (JH); Wang, Lyu-Han (LH); Cheng, Chau-Ming (CM); Ciou, Shih-Ci (SC); Lin, Szu-Ting (ST); Jheng, Ming-Yan (MY); Lin, Yun-Wei (YW);

Affiliation: Department of Biochemical Science and Technology, National Chiayi University, 300 Syuefu Road, Chiayi 600, Taiwan.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Molecular cancer therapeutics (Mol Cancer Ther), published in United States. (Language: eng)

Reference: 2008-Nov; vol 7 (issue 11) : pp 3632-41

Dates: Created 2008/11/12; Completed 2008/12/22;

PMID: 19001445, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Antineoplastic Agents - pharmacology
Carcinoma, Non-Small-Cell Lung - drug therapy; metabolism
Cell Line, Tumor
Humans
Lung Neoplasms - drug therapy; metabolism
MAP Kinase Kinase 1 - antagonists & inhibitors; metabolism
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Antineoplastic Agents (0) ; Quinazolines (0) ; gefitinib (184475-35-2) ; MAP Kinase Kinase 1 (EC 2.7.1.-) ; Mitogen-Activated Protein Kinase 1 (EC 2.7.1.37) ; Mitogen-Activated Protein Kinase 3 (EC 2.7.1.37) ; Rad51 Recombinase (EC 2.7.7.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-)

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