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

Ko, Jen-Chung; Hong, Jhao-Hao; Wang, Lyu-Han; Cheng, Chau-Ming; Ciou, Shih‐Ci; Lin, Szu‐Ting; Jheng, Ming-Yan; Lin, Yun‐Wei

doi:10.1158/1535-7163.mct-08-0578

Cited by 37 publications

(26 citation statements)

References 48 publications

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“…In lung cancer, high expression of Rad51 in tumor tissue is associated with an unfavorable prognosis (24). Our recent study has shown that the polycyclic hydrocarbon carcinogen benzo(a)pyrene can enhance the expression of Rad51 through the activation of ERK1/2 (45), and MEK1/2-ERK1/2 is the upstream signaling pathway to regulate the Rad51 expression, which is associated with the resistance to gefitinib, mitomycin C, and cisplatin in NSCLC (25,26).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, erlotinib-enhanced Rad51 protein instability is through 26S proteasome-mediated proteolysis in H1650 and A549 cells. Our previous studies indicated that MKK1/2-ERK1/2 signaling pathway is the upstream molecules to maintain the cellular Rad51 protein and mRNA levels in NSCLC cells (26). To determine whether activation of the PI3K-AKT signaling pathway was also involved in the maintaining of Rad51 protein and mRNA expression, the NSCLC cell lines were treated with various concentrations of PI3K inhibitors, wortmannin, or LY294002.…”

Section: Erlotinib Enhances Rad51 Protein Instability Through the Degmentioning

confidence: 99%

“…In lung cancer, high expression of Rad51 in tumor tissue is associated with an unfavorable prognosis (24). Our recent study has shown that the MEK1/2-ERK1/2 is the upstream signaling pathway in regulating the Rad51 expression (25,26). However, the role of Rad51 in regulating the response to erlotinib in different cell types of human NSCLC also remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

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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

Ciou

Jhan

et al. 2009

Molecular Cancer Research

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Erlotinib (Tarceva) is a selective epidermal growth factor receptor tyrosine kinase inhibitor in the treatment of human non-small cell lung cancer (NSCLC). In this study, we investigated the roles of ERK1/2 and AKT signaling pathways in regulating Rad51 expression and cytotoxic effects in different NSCLC cell lines treated with erlotinib. Erlotinib decreased cellular levels of phosphorylated ERK1/2, phosphorylated AKT, Rad51 protein, and mRNA in erlotinib-sensitive H1650, A549, and H1869 cells, leading to cell death via apoptosis, but these results were not seen in erlotinib-resistant H520 and H1703 cells. Erlotinib decreased Rad51 protein levels by enhancing Rad51 mRNA and protein instability. Enforced expression of constitutively active MKK1 or AKT vectors could restore Rad51 protein levels, which were inhibited by erlotinib, and decrease erlotinib-induced cytotoxicity. Knocking down endogenous Rad51 expression by si-Rad51 RNA transfection significantly enhanced erlotinib-induced cytotoxicity. In contrast, overexpression of Rad51 by transfection with Rad51 vector could protect the cells from cytotoxic effects induced by erlotinib. Blocking the activations of ERK1/2 and AKT by MKK1/2 inhibitor (U0126) and phosphoinositide 3-kinase inhibitor (wortmannin) suppressed the expression of Rad51 and enhanced the erlotinib-induced cell death in erlotinib-resistant cells. In conclusion, suppression of Rad51 may be a novel therapeutic modality in overcoming drug resistance of erlotinib in NSCLC. (Mol Cancer Res 2009;7(8):1378-89)

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Section: Discussionmentioning

confidence: 99%

Section: Erlotinib Enhances Rad51 Protein Instability Through the Degmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Ciou

Jhan

et al. 2009

Molecular Cancer Research

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“…First, ErbB-1 was found to directly interact with DNA-dependent protein kinase, catalytic subunit (Bandyopadhyay et al, 1998;Huang and Harari, 2000;Dittmann et al, 2005a,b;Das et al, 2006Das et al, , 2007, which is essential in the repair of DNA double strand breaks by nonhomologous end-joining (Khanna and Jackson, 2001). Second, ErbB-1 induces the expression of DNA repair genes such as XRCC1 (base-excision repair) through the Ras/Raf/MAPK pathway (Yacoub et al, 2001;Brem and Hall, 2005;Toulany et al, 2008) and Rad51 (involved in homologous recombination repair of double strand breaks) (Chinnaiyan et al, 2005;Ko et al, 2008). Third, ErbB-1 signaling modulates the activation of several DNA repair proteins, which includes DNA-dependent protein kinase, catalytic subunit (Toulany et al, 2006), and ATM (Golding et al, 2007).…”

Section: Evasion Of Immune Destruction (H-iv)mentioning

confidence: 99%

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Golen²,

et al. 2013

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“…Plasmid transfection of MKK1-CA (a constitutively active form of MKK1, ⌬N3/S218E/S222D) and MKK2-CA (a constitutively active form of MKK2, ⌬N4/S222E/S226D) was achieved as described previously (Ko et al, 2008b). Exponentially growing human lung cancer cells (10 6 ) were plated for 18 h before exposure to emodin and MMC for 24 h in RPMI 1640 complete medium.…”

Section: Methodsmentioning

confidence: 99%

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

Su¹,

Tsai²,

Kuo³

et al. 2009

Mol Pharmacol

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Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) is a natural anthraquinone derivative found in the roots and rhizomes of numerous plants. It is a tyrosine kinase inhibitor and has anticancer effects on lung cancer. Rad51 plays a central role in homologous recombination, and high levels of Rad51 expression are observed in chemo-or radioresistant carcinomas. Our previous studies have shown that the mitogen-activated protein kinase kinase (MKK) 1/2-extracellular signal-regulated kinase (ERK) 1/2 signal pathway maintains the expression of Rad51. Therefore, in this study, we hypothesized that emodin could enhance the effects of the antitumor antibiotic mitomycin C (MMC)-mediated cytotoxicity by decreasing the expression of Rad51 and the phosphorylation of ERK1/2. Exposure of the human non-small-cell lung cancer H1703 or A549 cell lines to emodin decreased the MMC-elicited phosphorylated ERK1/2 and Rad51 levels. Moreover, emodin significantly decreased the MMC-elicited Rad51 mRNA and protein levels by increasing the instability of Rad51 mRNA and protein. In emodin-and MMC-cotreated cells, ERK1/2 phosphorylation was enhanced by constitutively active MKK1/2 (MKK1/2-CA), thus increasing Rad51 protein levels and protein stability. The synergistic cytotoxic effects induced by emodin combined with MMC were remarkably decreased by MKK1-CA-mediated enhancement of ERK1/2 activation. Depletion of endogenous Rad51 expression by small interfering Rad51 RNA transfection significantly enhanced MMC-induced cell death and cell growth inhibition. In contrast, overexpression of Rad51 protects lung cancer cells from the synergistic cytotoxic effects induced by emodin and MMC. We conclude that suppression of Rad51 expression or a combination of emodin with chemotherapeutic agents may be considered as potential therapeutic modalities for lung cancer.Lung cancer is the leading cause of cancer-related death in the world and can be broadly classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) (Bhattacharjee et al., 2001). NSCLC accounts for approximately 85% of all lung cancers (Landis et al., 1999), and unlike SCLC, NSCLC is less sensitive to chemotherapeutic agents; the average 5-year survival rates are 10 to 15% . Mitomycin C (MMC) is an anticancer drug that forms monoadducts and intrastrand cross-links between the N-2 guanines of the d(CpG) sequence in the minor groove of DNA (Warren and Hamilton, 1996;Dronkert and Kanaar, 2001). MMC is typically used as a first-or second-line regimen to treat NSCLC and is often combined with other chemotherapeutic agents during advanced NSCLC treatment (Babiak et al., 2007). The therapeutic value of MMC depends on the ability of cells to remove DNA damage (McHugh et al., 2001).

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

Cited by 37 publications

References 48 publications

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

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

The Molecular Basis for the Pharmacokinetics and Pharmacodynamics of Curcumin and Its Metabolites in Relation to Cancer

Role of Rad51 Down-Regulation and Extracellular Signal-Regulated Kinases 1 and 2 Inactivation in Emodin and Mitomycin C-Induced Synergistic Cytotoxicity in Human Non–Small-Cell Lung Cancer Cells

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