Enhanced levels of double-strand DNA break repair proteins protect ovarian cancer cells against genotoxic stress-induced apoptosis

详细信息    查看全文

• 作者：Rajkumar Singh Kalra (2)
  Sharmila A Bapat (2)
  
• 关键词：SeOvCa progression model ; DSB ; repair ; HR and NHEJ pathways ; Aneuploidy
• 刊名：Journal of Ovarian Research
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：6
• 期：1
• 全文大小：1,230 KB
• 参考文献：1. Zhou BB, Bartek J: Targeting the checkpoint kinases: chemosensitization versus chemoprotection. / Nat Rev Cancer 2004, 4:216鈥?5. CrossRef
  2. Kastan MB, Bartek J: Cell-cycle checkpoints and cancer. / Nat 2004, 432:316鈥?23. CrossRef
  3. Berchuk CGARN: Integrated genomic analyses of ovarian carcinoma. / Nature 2011, 474:609鈥?15. CrossRef
  4. Gorgoulis VG, Vassiliou LV, Karakaidos P, Zacharatos P, Kotsinas A, Liloglou T, Venere M, Ditullio RA Jr, Kastrinakis NG, Levy B, Kletsas D, Yoneta A, Herlyn M, Kittas C, Halazonetis TD: Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. / Nature 2005, 434:907鈥?13. CrossRef
  5. Halazonetis TD, Gorgoulis VG, Bartek J: An oncogene-induced DNA damage model for cancer development. / Sci 2008, 319:1352鈥?355. CrossRef
  6. Kalra RS, Bapat SA: Expression proteomics predicts loss of RXR-纬 during progression of epithelial ovarian cancer. / PLoS ONE 2013,8(8):e70398. CrossRef
  7. Bapat SA, Mali AM, Koppikar CB, Kurrey NK: Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer. / Cancer Res 2005, 65:3025鈥?029.
  8. Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. / Cell 2011, 144:646鈥?74. CrossRef
  9. Wu MH, Yung BY: UV stimulation of nucleophosmin/B23 expression is an immediate-early gene response induced by damaged DNA. / J Biol Chem 2002, 277:48234鈥?8240. CrossRef
  10. Colombo E, Bonetti P, Lazzerini Denchi E, Martinelli P, Zamponi R, Marine JC, Helin K, Falini B, Pelicci PG: Nucleophosmin is required for DNA integrity and p19Arf protein stability. / Mol Cell Biol 2005, 25:8874鈥?886. CrossRef
  11. Koike A, Nishikawa H, Wu W, Okada Y, Venkitaraman AR, Ohta T: Recruitment of phosphorylated NPM1 to sites of DNA damage through RNF8-dependent ubiquitin conjugates. / Cancer Res 2010, 70:6746鈥?756. CrossRef
  12. Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW: H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. / Mol Cell 2006,21(2):201鈥?14. CrossRef
  13. Sonoda E, Hochegger H, Saberi A, Taniguchi Y, Takeda S: Differential usage of onhomologous end-joining and homologous recombination in double strand break repair. / DNA Repair 2006, 5:1021鈥?029. CrossRef
  14. Hopfner KP, Craig L, Moncalian G, Zinkel RA, Usui T, Owen BA, Karcher A, Henderson B, Bodmer JL, McMurray CT, Carney JP, Petrini JH, Tainer JA: The Rad50 zinc-hook is a structure joining Mre11 complexes in DNA recombination and repair. / Nature 2002, 418:562鈥?66. CrossRef
  15. Boulton SJ, Jackson SP: Components of the Ku-dependent non-homologous end-joining pathway are involved in telomeric length maintenance and telomeric silencing. / EMBO J 1998, 17:819鈥?28. CrossRef
  16. Wani AA, Sharma N, Shouche YS, Bapat SA: Nuclear鈥搈itochondrial genomic profiling reveals a pattern of evolution in epithelial ovarian tumor stem cells. / Oncogene 2006, 25:6336鈥?344. CrossRef
  17. Ribaudo R, Gilman M, Kingston RE, Choczynski P, Sacchi N: Preparation of RNA from tissues and cells. / Curr Protoc Immunol 2001,10(10):11.
  18. Kurrey NK, Jalgaonkar SP, Joglekar AV, Ghanate AD, Chaskar PD, Doiphode RY, Bapat SA: Snail and Slug mediate radio- and chemo-resistance by antagonizing p53-mediated apoptosis and acquiring a stem-like phenotype in ovarian cancer cells. / Stem Cells 2009, 27:2059鈥?068. CrossRef
  19. Sharma N, Jadhav SP, Bapat SA: CREBBP re-arrangements affect protein function and lead to aberrant neuronal differentiation. / Differentiation 2010, 79:218鈥?31. CrossRef
  20. Bapat SA, Krishnan A, Ghanate AD, Kusumbe AP, Kalra RS: Gene expression: protein interaction systems network modeling identifies transformation-associated molecules and pathways in ovarian cancer. / Cancer Res 2010, 70:4809鈥?819. CrossRef
  21. Li Z, Van Calcar S, Qu C, Cavenee WK, Zhang MQ, Ren B: A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. / Proc Natl Acad Sci U S A 2003, 8:164鈥?169.
  22. Dubik D, Dembinski TC, Shiu RP: Stimulation of c-myc oncogene expression associated with estrogen-induced proliferation of human breast cancer cells. / Cancer Res 1987, 47:6517鈥?521.
  23. Dubik D, Shiu RP: Transcriptional regulation of c-myc oncogene expression by estrogen in hormone-responsive human breast cancer cells. / J Biol Chem 1988, 263:12705鈥?2708.
  24. Eastman A, Barry MA: Interaction of trans-diamminedichloroplatinum(II) with DNA: formation of monofunctional adducts and their reaction with glutathione. / Biochem 1987, 26:3303鈥?307. CrossRef
  25. Colombo E, Marine JC, Danovi D, Falini B, Pelicci PG: Nucleophosmin regulates the stability and transcriptional activity of p53. / Nat Cell Biol 2002, 4:529鈥?33. CrossRef
  26. Tokuyama Y, Horn HF, Kawamura K, Tarapore P, Fukasawa K: Specific phosphorylation of nucleophosmin on Thr199 by cyclin-dependent kinase 2-cyclin E and its role in centrosome duplication. / J Bio Chem 2001, 276:21529鈥?1537. CrossRef
  27. Ahmed AA, Etemadmoghadam D, Temple J, Lynch AG, Riad M, Sharma R, Stewart C, Fereday S, Caldas C, Defazio A, Bowtell D, Brenton JD: Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. / J Pathol 2010, 221:49鈥?6. CrossRef
  28. Wojnarowicz PM, Oros KK, Quinn MC, Arcand SL, Gambaro K, Madore J, Birch AH, de Ladurantaye M, Rahimi K, Provencher DM, Mes-Masson AM, Greenwood CM, Tonin PN: The genomic landscape of TP53 and p53 annotated high grade ovarian serous carcinomas from a defined founder population associated with patient outcome. / PLoS One 2012, 7:e45484. CrossRef
  29. Kuhn E, Kurman RJ, Vang R, Sehdev AS, Han G, Soslow R, Wang TL, Shih Ie M: TP53 mutations in serous tubal intraepithelial carcinoma and concurrent pelvic high-grade serous carcinoma: evidence supporting the clonal relationship of the two lesions. / J Pathol 2012, 226:421鈥?26. CrossRef
  
• 作者单位：Rajkumar Singh Kalra (2)
  Sharmila A Bapat (2)
  
  2. National Centre for Cell Science, NCCS Complex, Pune University Campus, Ganeshkhind, Pune, 411 007, India
  
• ISSN：1757-2215

文摘

Background Earlier, proteomic profiling of a Serous Ovarian Carcinoma (SeOvCa) progression model in our lab had identified significantly enriched expression of three double-strand break (DSB) -repair proteins viz. RAD50, NPM1, and XRCC5 in transformed cells over pre-transformed, non-tumorigenic cells. Analysis of the functional relevance of enhanced levels of these proteins was explored in transformed ovarian cancer cells. Methods Expression profiling, validation and quantitation of the DSB-repair proteins at the transcriptional and protein levels were carried out. Further analyses included identification of their localization, distribution and modulation on exposure to Estradiol (E2) and cisplatin. Effects on silencing of each of these under conditions of genomic-stress were studied with respect to apoptosis, alterations in nuclear morphology and DNA fragmentation; besides profiling known mitotic and spindle check-point markers in DSB-repair. Results We identified that levels of these DSB-repair proteins were elevated not only in our model, but generally in cancer and are specifically triggered in response to genotoxic stress. Silencing of their expression led to aberrant DSB repair and consequently, p53/p21 mediated apoptosis. Further compromised functionality generated genomic instability. Conclusions Present study elucidates a functional relevance of NPM1, RAD50 and XRCC5 DSB-repair proteins towards ensuring survival and evasion of apoptosis during ovarian transformation, emphasizing their contribution and association with disease progression in high-grade SeOvCa.