Current status of excision repair cross complementing-group 1 (ERCC1) in cancer.
ABSTRACT Cisplatin, carboplatin and oxaliplatin are some of the most widely used anti-cancer agents in solid tumours. The cytotoxicity of platinating agents is directly related to their ability to cause DNA intra-strand crosslinks that trigger a series of intracellular events that ultimately result in cell death. DNA intra-strand crosslinks are processed and repaired by the nucleotide excision repair pathway. It is now clear that nucleotide excision repair (NER) capacity may have a major impact on the emergence of resistance, normal tissue tolerance and patient outcomes. ERCC1 is a key player in NER. In this review, we provide an overview of mammalian NER and then focus on biochemical, structural and pre-clinical aspects of ERCC1. We then present current clinical evidence implicating ERCC1 as a predictive and prognostic marker in cancer. Early evidence also suggests that ERCC1 or the pathways involved in the regulation of ERCC1 expression may be attractive anti-cancer targets. Such agents are expected to potentiate the cytotoxicity of platinating agents and could have a major impact on cancer therapy.
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ABSTRACT: Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.PLoS ONE 10(3):e0119614. DOI:10.1371/journal.pone.0119614 · 3.53 Impact Factor
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ABSTRACT: This study aimed to evaluate the biological functions of excision repair cross complementation goup 1 (ERCC1) in cell proliferation, cell cycle, invasion and cisplatin response of non-small cell lung cancer (NSCLC) cells. Firstly, ERCC1 gene was successfully transfected into H1299 cells by gene cloning and transfection techniques. Then, cell proliferation was determined with the cell growth curve and colony-forming assays. Flow cytometry (FCM) was employed to investigate the cell cycle distribution. The ability of cell invasion was estimated by means of Matrigel invasion assays. Response of NSCLC cells to cisplatin was detected utilizing MTT assays, and the intracellular drug concentrations were determined by the high performance liquid chromatography (HPLC) analysis. Expression of the two cell membrane proteins, P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP), was also evaluated utilizing FCM technique. By contrast, ERCC1 expression in the NSCLC A549 cells was silenced by small interfering RNA (siRNA) through RNAi technique. In addition, the cytotoxic effect of cisplatin on A549 cells was detected by MTT assays. In the present study, the results demonstrated that ERCC1 had no effect on cell proliferation, cell cycle and the ability of invasion, but showed significant impact on cisplatin response of the NSCLC H1299 cells. Furthermore, siRNA-induced suppression of ERCC1 evidently enhanced sensitivity to cisplatin of NSCLC A549 cells. Therefore, it is confirmed that ERCC1 is a chemotherapy-tolerating gene and a promising predictor in tailoring chemotherapy of NSCLC.International Journal of Oncology 11/2014; 46(2). DOI:10.3892/ijo.2014.2784 · 2.77 Impact Factor
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ABSTRACT: Nucleotide excision repair (NER) is involved in the repair of DNA damages caused by platinum derivatives and has been shown to decrease their cytotoxic activity. As protein-protein interactions are essential for NER activity, we transfected human cancer cell lines (A549 and HCT116) with plasmids coding the amino-acid sequences corresponding to the interacting domains between ERCC1 and XPA as well as ERCC1 and XPF, all NER proteins. Using MTT assay and Annexin V staining, we showed that transfected A549 cells were sensitized 1.2-2.2-fold to carboplatin and transfected HCT116 cells 1.4-5.4-fold to oxaliplatin in vitro. Transfected cells had also modified in vivo sensitivity to the same drugs. Finally, in particular cell models for the interaction between ERCC1 and XPF showed decreased DNA repair as shown by increase ɣH2AX-staining after exposure to mitomycin C, as well as increased genomic instability as determined by comparative genomic hybridization study. Our results indicate that the interacting peptides act as dominant negatives and decrease NER activity through the inhibition of protein-protein interactions.This article is protected by copyright. All rights reserved.Clinical and Experimental Pharmacology and Physiology 08/2014; 41(10). DOI:10.1111/1440-1681.12282 · 2.41 Impact Factor