Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2011

Open Access 01-12-2011 | Research

Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells

Authors: Qi-En Wang, Keisha Milum, Chunhua Han, Yi-Wen Huang, Gulzar Wani, Jürgen Thomale, Altaf A Wani

Published in: Molecular Cancer | Issue 1/2011

Login to get access

Abstract

Background

While platinum-based chemotherapeutic agents are widely used to treat various solid tumors, the acquired platinum resistance is a major impediment in their successful treatment. Since enhanced DNA repair capacity is a major factor in conferring cisplatin resistance, targeting of DNA repair pathways is an effective stratagem for overcoming cisplatin resistance. This study was designed to delineate the role of nucleotide excision repair (NER), the principal mechanism for the removal of cisplatin-induced DNA intrastrand crosslinks, in cisplatin resistance and reveal the impact of DNA repair interference on cisplatin sensitivity in human ovarian cancer cells.

Results

We assessed the inherent NER efficiency of multiple matched pairs of cisplatin-sensitive and -resistant ovarian cancer cell lines and their expression of NER-related factors at mRNA and protein levels. Our results showed that only the cisplatin-resistant ovarian cancer cell line PEO4 possessed an increased NER capacity compared to its inherently NER-inefficient parental line PEO1. Several other cisplatin-resistant cell lines, including CP70, CDDP and 2008C13, exhibited a normal and parental cell-comparable NER capacity for removing cisplatin-induced DNA intrastrand cross-links (Pt-GG). Concomitant gene expression analysis revealed discordance in mRNA and protein levels of NER factors in various ovarian cancer cell lines and NER proteins level were unrelated to the cisplatin sensitivity of these cell lines. Although knockdown of NER factors was able to compromise the NER efficiency, it only caused a minimal effect on cisplatin sensitivity. On the contrary, downregulation of BRCA2, a critical protein for homologous recombination repair (HRR), significantly enhanced the efficacy of cisplatin in killing ovarian cancer cell line PEO4.

Conclusion

Our studies indicate that the level of NER factors in ovarian cancer cell lines is neither a determinant of their NER capacity nor of the sensitivity to cisplatin, and suggest that manipulation of the HRR but not the NER factor expression provides an effective strategy for sensitizing cisplatin-resistant tumors to platinating agents.
Appendix
Available only for authorised users
Literature
1.
Cohen SM, Lippard SJ: Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol. 2001, 67: 93-130. full_textCrossRefPubMed
2.
Jung Y, Lippard SJ: Direct cellular responses to platinum-induced DNA damage. Chem Rev. 2007, 107: 1387-1407. 10.1021/cr068207jCrossRefPubMed
3.
Kartalou M, Essigmann JM: Recognition of cisplatin adducts by cellular proteins. Mutat Res. 2001, 478: 1-21. 10.1016/S0027-5107(01)00142-7CrossRefPubMed
4.
Huang JC, Zamble DB, Reardon JT, Lippard SJ, Sancar A: HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease. pnas. 1994, 91: 10394-10398. 10.1073/pnas.91.22.10394PubMedCentralCrossRefPubMed
5.
Zamble DB, Mu D, Reardon JT, Sancar A, Lippard SJ: Repair of cisplatin-DNA adducts by the mammalian excision nuclease. Biochemistry. 1996, 35: 10004-10013. 10.1021/bi960453+CrossRefPubMed
6.
McHugh PJ, Spanswick VJ, Hartley JA: Repair of DNA interstrand crosslinks: molecular mechanisms and clinical relevance. Lancet Oncol. 2001, 2: 483-490. 10.1016/S1470-2045(01)00454-5CrossRefPubMed
7.
Petit C, Sancar A: Nucleotide excision repair: From E.coli to man. Biochimie. 1999, 81: 15-25. 10.1016/S0300-9084(99)80034-0CrossRefPubMed
8.
Araujo SJ, Tirode F, Coin F, Pospiech H, Syvaoja JE, Stucki M, Hubscher U, Egly JM, Wood RD: Nucleotide excision repair of DNA with recombinant human proteins: definition of the minimal set of factors, active forms of TFIIH, and modulation by CAK. Genes Dev. 2000, 14: 349-359.PubMedCentralPubMed
9.
Araujo SJ, Nigg EA, Wood RD: Strong functional interactions of TFIIH with XPC and XPG in human DNA nucleotide excision repair, without a preassembled repairosome. Mol Cell Biol. 2001, 21: 2281-2291. 10.1128/MCB.21.7.2281-2291.2001PubMedCentralCrossRefPubMed
10.
Volker M, Mone MJ, Karmakar P, Van Hoffen A, Schul W, Vermeulen W, Hoeijmakers JH, van Driel R, van Zeeland AA, Mullenders LH: Sequential assembly of the nucleotide excision repair factors in vivo. Mol Cell. 2001, 8: 213-224. 10.1016/S1097-2765(01)00281-7CrossRefPubMed
11.
Sugasawa K, Ng JMY, Masutani C, Iwai S, Van der Spek P, Eker A, Hanaoka F, Bootsma D, Hoeijmakers JH: Xeroderma pigmentosum group C complex is the initiator of global genome nucleotide excision repair. Mol Cell. 1998, 2: 223-232. 10.1016/S1097-2765(00)80132-XCrossRefPubMed
12.
Moynahan ME, Pierce AJ, Jasin M: BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001, 7: 263-272. 10.1016/S1097-2765(01)00174-5CrossRefPubMed
13.
Sakai W, Swisher EM, Jacquemont C, Chandramohan KV, Couch FJ, Langdon SP, Wurz K, Higgins J, Villegas E, Taniguchi T: Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 2009, 69: 6381-6386. 10.1158/0008-5472.CAN-09-1178PubMedCentralCrossRefPubMed
14.
Chetrit A, Hirsh-Yechezkel G, Ben-David Y, Lubin F, Friedman E, Sadetzki S: Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer. J Clin Oncol. 2008, 26: 20-25. 10.1200/JCO.2007.11.6905CrossRefPubMed
15.
Saldivar JS, Wu X, Follen M, Gershenson D: Nucleotide excision repair pathway review I: implications in ovarian cancer and platinum sensitivity. Gynecol Oncol. 2007, 107: S56-S71. 10.1016/j.ygyno.2007.07.043CrossRefPubMed
16.
Johnson SW, Perez RP, Godwin AK, Yeung AT, Handel LM, Ozols RF, Hamilton TC: Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines. Biochem Pharmacol. 1994, 47: 689-697. 10.1016/0006-2952(94)90132-5CrossRefPubMed
17.
Masuda H, Tanaka T, Matsuda H, Kusaba I: Increased removal of DNA-bound platinum in a human ovarian cancer cell line resistant to cis-diamminedichloroplatinum(II). Cancer Res. 1990, 50: 1863-1866.PubMed
18.
Parker RJ, Eastman A, Bostick-Bruton F, Reed E: Acquired cisplatin resistance in human ovarian cancer cells is associated with enhanced repair of cisplatin-DNA lesions and reduced drug accumulation. J Clin Invest. 1991, 87: 772-777. 10.1172/JCI115080PubMedCentralCrossRefPubMed
19.
Masuda H, Ozols RF, Lai GM, Fojo A, Rothenberg M, Hamilton TC: Increased DNA repair as a mechanism of acquired resistance to cis-diamminedichloroplatinum(II) in human ovarian cancer cell lines. Cancer Res. 1988, 48: 5713-5716.PubMed
20.
Barakat BM, Wang QE, Han C, Milum K, Yin DT, Zhao Q, Wani G, Arafa el-SA, El-Mahdy MA, Wani AA: Overexpression of DDB2 enhances the sensitivity of human ovarian cancer cells to cisplatin by augmenting cellular apoptosis. Int J Cancer. 2010, 127: 977-988.PubMedCentralPubMed
21.
Koc A, Wheeler LJ, Mathews CK, Merrill GF: Hydroxyurea arrests DNA replication by a mechanism that preserves basal dNTP pools. J Biol Chem. 2004, 279: 223-230. 10.1074/jbc.M303952200CrossRefPubMed
22.
Lehmann AR, Stevens S: A rapid procedure for measurement of DNA repair in human fibroblasts and for complementation analysis of xeroderma pigmentosum cells. Mutat Res. 1980, 69: 177-190. 10.1016/0027-5107(80)90187-6CrossRefPubMed
23.
Liedert B, Pluim D, Schellens J, Thomale J: Adduct-specific monoclonal antibodies for the measurement of cisplatin-induced DNA lesions in individual cell nuclei. Nucleic Acids Res. 2006, 34: e47- 10.1093/nar/gkl051PubMedCentralCrossRefPubMed
24.
Wang QE, Zhu Q, Wani G, El-Mahdy MA, Li J, Wani AA: DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation. Nucleic Acids Res. 2005, 33: 4023-4034. 10.1093/nar/gki684PubMedCentralCrossRefPubMed
25.
Sakai W, Swisher EM, Karlan BY, Agarwal MK, Higgins J, Friedman C, Villegas E, Jacquemont C, Farrugia DJ, Couch FJ, Urban H, Taniguchi T: Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature. 2008, 451: 1116-1120. 10.1038/nature06633PubMedCentralCrossRefPubMed
26.
Stewart DJ: Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 2007, 63: 12-31. 10.1016/j.critrevonc.2007.02.001CrossRefPubMed
27.
Arora S, Kothandapani A, Tillison K, Kalman-Maltese V, Patrick SM: Downregulation of XPF-ERCC1 enhances cisplatin efficacy in cancer cells. DNA Repair (Amst). 2010, 9: 745-753. 10.1016/j.dnarep.2010.03.010CrossRef
28.
Martin LP, Hamilton TC, Schilder RJ: Platinum resistance: the role of DNA repair pathways. Clin Cancer Res. 2008, 14: 1291-1295. 10.1158/1078-0432.CCR-07-2238CrossRefPubMed
29.
Ferry KV, Hamilton TC, Johnson SW: Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol. 2000, 60: 1305-1313. 10.1016/S0006-2952(00)00441-XCrossRefPubMed
30.
Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC: Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res. 2003, 63: 1311-1316.PubMed
31.
Wu X, Fan W, Xu S, Zhou Y: Sensitization to the cytotoxicity of cisplatin by transfection with nucleotide excision repair gene xeroderma pigmentosun group A antisense RNA in human lung adenocarcinoma cells. Clin Cancer Res. 2003, 9: 5874-5879.PubMed
32.
Orelli B, McClendon TB, Tsodikov OV, Ellenberger T, Niedernhofer LJ, Scharer OD: The XPA-binding domain of ERCC1 is required for nucleotide excision repair but not other DNA repair pathways. J Biol Chem. 2010, 285: 3705-3712. 10.1074/jbc.M109.067538PubMedCentralCrossRefPubMed
33.
Usanova S, Piee-Staffa A, Sied U, Thomale J, Schneider A, Kaina B: Cisplatin sensitivity of testis tumour cells is due to deficiency in interstrand-crosslink repair and low ERCC1-XPF expression. Mol Cancer. 2010, 9: 248- 10.1186/1476-4598-9-248PubMedCentralCrossRefPubMed
34.
Johnson SW, Swiggard PA, Handel LM, Brennan JM, Godwin AK, Ozols RF, Hamilton TC: Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells. Cancer Res. 1994, 54: 5911-5916.PubMed
35.
McGurk CJ, Cummings M, Koberle B, Hartley JA, Oliver RT, Masters JR: Regulation of DNA repair gene expression in human cancer cell lines. J Cell Biochem. 2006, 97: 1121-1136. 10.1002/jcb.20711CrossRefPubMed
36.
Muotri AR, Marchetto MC, Suzuki MF, Okazaki K, Lotfi CF, Brumatti G, Amarante-Mendes GP, Menck C: Low amounts of the DNA repair XPA protein are sufficient to recover UV-resistance. Carcinogenesis. 2002, 23: 1039-1046. 10.1093/carcin/23.6.1039CrossRefPubMed
37.
Koberle B, Roginskaya V, Wood RD: XPA protein as a limiting factor for nucleotide excision repair and UV sensitivity in human cells. DNA Repair (Amst). 2006, 5: 641-648. 10.1016/j.dnarep.2005.12.001CrossRef
38.
Altaha R, Liang X, Yu JJ, Reed E: Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med. 2004, 14: 959-970.PubMed
39.
Olaussen KA, Dunant A, Fouret P, Brambilla E, Andre F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH, Stahel R, Sabatier L, Pignon JP, Tursz T, Le Chevalier T, Soria JC: DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med. 2006, 355: 983-991. 10.1056/NEJMoa060570CrossRefPubMed
40.
Ahmad A, Robinson AR, Duensing A, van Drunen E, Beverloo HB, Weisberg DB, Hasty P, Hoeijmkers JH, Niedernhofer LJ: ERCC1-XPF endonuclease facilitates DNA double-strand break repair. Mol Cell Biol. 2008, 28: 5082-5092. 10.1128/MCB.00293-08PubMedCentralCrossRefPubMed
41.
Niedernhofer LJ, Odijk H, Budzowska M, van Drunen E, Maas A, Theil AF, de Wit J, Jaspers NG, Beverloo HB, Hoeijmakers JH, Kanaar R: The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol. 2004, 24: 5776-5787. 10.1128/MCB.24.13.5776-5787.2004PubMedCentralCrossRefPubMed
42.
Cummings M, Higginbottom K, McGurk CJ, Wong OG, Koberle B, Oliver RT, Masters JR: XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Biochem Pharmacol. 2006, 72: 166-175. 10.1016/j.bcp.2006.04.025CrossRefPubMed
43.
Koberle B, Roginskaya V, Zima KS, Masters JR, Wood RD: Elevation of XPA protein level in testis tumor cells without increasing resistance to cisplatin or UV radiation. Mol Carcinog. 2008, 47: 580-586. 10.1002/mc.20418CrossRefPubMed
Metadata
Title
Differential contributory roles of nucleotide excision and homologous recombination repair for enhancing cisplatin sensitivity in human ovarian cancer cells
Authors
Qi-En Wang
Keisha Milum
Chunhua Han
Yi-Wen Huang
Gulzar Wani
Jürgen Thomale
Altaf A Wani
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2011
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-10-24

Other articles of this Issue 1/2011

Molecular Cancer 1/2011 Go to the issue

Research

Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer

Research

Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes

Research

Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy

Short communication

A switch in RND3-RHOA signaling is critical for melanoma cell invasion following mutant-BRAF inhibition

Research

The monoclonal antibody Zt/f2 targeting RON receptor tyrosine kinase as potential therapeutics against tumor growth-mediated by colon cancer cells

Research

Hyperactivation of NF-κB via the MEK signaling is indispensable for the inhibitory effect of cAMP on DNA damage-induced cell death
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits