Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells

Ko, Jen-Chung; Su, Ying-Jhen; Lin, Szu‐Ting; Jhan, Jhih-Yuan; Ciou, Shih‐Ci; Cheng, Chao‐Min; Lin, Yun‐Wei

doi:10.1016/j.bcp.2009.09.024

Cited by 66 publications

(43 citation statements)

References 42 publications

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“…In addition, an ionizing radiation-induced ERCC1 increase in prostate cancer cells also depended on ERK activation (Yacoub et al, 2003). Moreover, blocking ERK activation with a MEK inhibitor decreased cisplatin-induced ERCC1 protein levels in lung cancer cell lines (Ko et al, 2010). In a similar way, our data indicate that the MAPK pathway regulates ERCC1 mRNA and protein levels following cisplatin treatment in melanoma cells.…”

Section: Discussionsupporting

confidence: 72%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. Melanoma is the second most common cancer among young adults in the UK, where incidence rates have more than quadrupled since the 1970s. Increased expression of a number of DNA repair genes has been reported in melanoma and this likely contributes to its extreme resistance to conventional DNA-damaging chemotherapeutics. One such chemotherapeutic that is effective against a range of other cancers, but not melanoma, is cisplatin. The DNA repair proteins ERCC1 and XPF are needed to remove cisplatin-induced DNA damage and we have investigated the response of these proteins to cisplatin in melanoma. The expression of both genes is induced by cisplatin. Use of a MEK inhibitor showed that ERCC1, but not XPF induction was regulated by the mitogen-activated protein kinase (MAPK) pathway, with reduction in expression of DUSP6, the phosphatase that inactivates the extracellular signal-regulated kinase (ERK), being particularly important. DUSP6 overexpression prevented cisplatin induction of both ERCC1 and XPF, resulting in increased sensitivity to cisplatin. A novel ERCC1 mRNA was found that initiated upstream of the normal transcription initiation site, and was strongly regulated by both cisplatin and the MAPK pathway and its role in cisplatin resistance merits further study. The cisplatin induction of ERCC1 and XPF provides important insights into the resistance of melanoma to DNA-damaging chemotherapeutics, which is one of the major obstacles to melanoma treatment.

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Section: Discussionsupporting

confidence: 72%

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Melton

2011

Oncogene

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“…One limitation of the present study is that we did not examine the correlation between Snail and ERCC1 in an in vitro study and did not examine other markers such as ERK1/2, which has been reported to regulate Snail expression (27). Another limitation is that the sample size for immunohistochemical analysis was small and the study was retrospective.…”

Section: Discussionmentioning

confidence: 91%

Co-expression of ERCC1 and Snail is a prognostic but not predictive factor of cisplatin-based neoadjuvant chemotherapy for bladder cancer

et al. 2012

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Abstract. Neoadjuvant chemotherapy (NC) for bladder cancer has been reported to significantly improve the 5-year survival rate. The aim of the present study was to examine the roles of ERCC1 and Snail in determining the response to chemotherapy in bladder cancer treated with NC and radical cystectomy (RC). The expression of the Snail and ERCC1 proteins was determined by immunohistochemical staining of specimens obtained from 58 patients with bladder tumors treated with NC and RC. The correlation between clinical response and the expression of Snail and ERCC1 was investigated. Snail and ERCC1 were co-expressed in 24 (41.4%) of the 58 patients. A marked correlation was found between the expression of Snail and ERCC1 (P=0.001). The co-expression of Snail and ERCC1 was not able to predict pathological complete response (P=0.202). Results of the univariate analysis revealed that the co-expression of Snail and ERCC1 predicted shorter diseasefree survival (DFS) and overall survival (OS) than the negative expression of Snail and/or ERCC1. Moreover, the co-expression of ERCC1 and Snail was the only predictive factor for both DFS (P=0.029) and OS (P=0.040). The expression of Snail was correlated with that of ERCC1 and the co-expression of Snail and ERCC1 was the only significant predictive factor of shorter DFS and OS in patients with bladder cancer treated with NC and RC. IntroductionBladder cancer is the fourth most common cancer in males in the USA (1). For muscle-invasive bladder cancer, radical cystectomy (RC) and urinary diversion are the gold standard of therapy in many parts of the world (1-3). Neoadjuvant chemotherapy (NC) with cisplatin-based combination chemotherapy significantly improved the 5-year survival rate in two meta-analysis studies (4,5) and pathological complete response (pCR) with NC was correlated with survival (6,7). Although a number of studies have discussed factors which predict pCR or a favorable survival rate (8-10), none of the factors has been proven in a clinical study.The excision repair cross-complementing group 1 (ERCC1) gene is located on chromosome 19q13.2-q13.3. The ERCC1 protein is crucial in the nucleotide excision repair pathway (11,12). In a previous study, we reported that ERCC1 may predict the prognosis of chemoradiotherapy for bladder cancer and that it was correlated with radiation rather than cisplatin resistance in an in vitro study (13). A correlation between ERCC1 and bladder cancer has been reported (14-17), but whether ERCC1 is capable of predicting a favorable survival rate in patients with advanced bladder cancer treated with cisplatin-based chemotherapy is controversial.The endothelial-mesenchymal transition (EMT) is significant in invasive bladder cancer (18,19). Mesenchymal markers, including N-cadherin, Zeb1, Snail and Slug, suppress the expression of E-cadherin and are correlated with radiation and cisplatin resistance in numerous types of cancer (20)(21)(22). In their study, Hsu et al reported that Snail regulated the expression of ERCC1 and that the co-expressi...

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“…Emodin is an anthraquinone, is naturally distributed and well known to possess broad pharmacological activities [2]. Emodin (D1) has been reported to inhibit the proliferation of many cancer cells which include; Colon cancer [3] [4], breast cancer [5] [6], gall bladder cancer [7] [8], pancreatic cancer [9], lung cancer [10] [11] and human cervical cancer [12]. Poor bioavailability and toxicity in vivo have been documented to limit emodin as cancer chemotherapy [13].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and ADMET Study of Emodin Derivatives as Anticancer Inhibitors of NAT2, COX2 and TOP1 Enzymes

Shadrack¹,

Ndesendo²

2017

CMB

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Over the past years natural products and/or their derivatives have continued to provide cancer chemotherapeutics. Glycosides derivatives of emodin are known to possess anticancer activities. An in silico study was carried out to evaluate emodin derivatives as inhibitors of Arylamine N-Acetyltransferase 2, Cyclooxygenase 2 and Topoisomerase 1 enzymes, predict their pharmacokinetics and explore their bonding modes. Molecular docking study suggested that D2, D5, D6 and D9 to be potent inhibitors of NAT2, while D8 was suggested to be a potent inhibitor of TOP1. Derivatives D2, D5, D6 and D9 bind to the same pocket with different binding conformation. Pharmacokinetic study suggested that selected emodin derivatives can be potential cancer chemotherapeutic agent. Physicochemical parameters such density, balaban index, surface tension, logP and molar reflectance correlated to compounds activity. These finding provides a potential strategy towards developing NAT2 and TOP1 inhibitors.

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Suppression of ERCC1 and Rad51 expression through ERK1/2 inactivation is essential in emodin-mediated cytotoxicity in human non-small cell lung cancer cells

Cited by 66 publications

References 42 publications

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Cisplatin regulates the MAPK kinase pathway to induce increased expression of DNA repair gene ERCC1 and increase melanoma chemoresistance

Co-expression of ERCC1 and Snail is a prognostic but not predictive factor of cisplatin-based neoadjuvant chemotherapy for bladder cancer

Molecular Docking and ADMET Study of Emodin Derivatives as Anticancer Inhibitors of NAT2, COX2 and TOP1 Enzymes

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