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Differential regulation of the response to DNA damage in Ewing's sarcoma cells by ETS1 and EWS/FLI-1

Oncogene volume 21, pages 2890–2895 (2002)Cite this article

Abstract

Ewing's sarcoma (EWS) cells contain levels of poly(ADP-ribose) polymerase (PARP) significantly higher than other eukaryotic cells. Previously, we cloned the PARP gene promoter region from EWS cells, showed that it contained multiple ETS-binding sites and demonstrated a positive regulation of PARP by ETS1. We now report that, contrary to ETS1, EWS/FLI-1, an aberrant ETS transcription factor present in most EWS cells, is a negative effector of PARP transcription. Because PARP levels have been associated with cellular resistance or sensitivity to genotoxic agents, we studied the effect of modifying PARP levels in EWS cells on their response to DNA damage by modulating the expression of ETS1 or EWS/FLI-1 using antisense methodology. Results show that stable down-regulation of ETS1 increases the resistance of EWS cells to various genotoxic agents, whereas down-regulation of EWS/FLI-1 has pro-apoptotic effects. Because down-regulation EWS/FLI-1 does not dramatically change PARP levels, these results suggest a direct effect for EWS/FLI-1 in the DNA damage response of EWS cells. Since expression of the aberrant fusion proteins by EWS cells is essential for maintaining their neoplastic phenotype, our results suggest that the use of antisense oligonucleotides in combination with chemotherapeutic agents or radiation may be doubly effective by causing both an increase in sensitivity to therapeutic agents and a simultaneous down-regulation, or reversion, of the neoplastic phenotype of EWS cells.

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Abbreviations

AS:

antisense

CAT:

chloramphenicol acetyl transferase

EWS:

Ewing's sarcoma

IR:

ionizing radiation

ODN:

oligodeoxynucleotide

PARP:

poly(ADP-ribose) polymerase

PCR:

polymerase chain reaction

SC:

sequence-scrambled ODNs

References

  • Alexandrow MG, Moses HL . 1995 Cancer Res. 55: 1452–1457

  • Arvand A, Denny CT . 2001 Oncogene 20: 5747–5754

  • Boulukos KE, Pognonec P, Rabault B, Begue A, Ghysdael J . 1989 Mol. Cell. Biol. 9: 5718–5721

  • Bories JC, Willerford DM, Grevin D, Davidson L, Camus A, Martin P, Stehelin D, Alt FW . 1995 Nature 377: 635–638

  • De Alava E, Panizo A, Antonescu CR, Huvos AG, Pardo-Mindan FJ, Barr FG, Ladanyi M . 2000 Am. J. Pathol. 156: 849–855

  • Dohjima T, Ohno T, Banno Y, Nozawa Y, Wen-yi Y, Shimizu K . 2000 Br. J. Cancer 82: 16–19

  • Gokhale PC, McRae D, Monia BP, Bagg A, Rahman A, Dritschilo A, Kasid U . 1999 Antisense Nucleic Acid Drug Dev. 9: 191–201

  • Gokhale PC, Soldatenkov V, Wang FH, Rahman A, Dritschilo A, Kasid U . 1997 Gene Ther. 4: 1289–1299

  • Hahm KB, Cho K, Lee C, Im YH, Chang J, Choi SG, Sorensen PH, Thiele CJ, Kim SJ . 1999 Nat. Genet. 23: 222–227

  • Huang CC, Papas TS, Bhat NK . 1997 Oncogene 15: 851–856

  • Im YH, Kim HT, Lee C, Poulin D, Welford S, Sorensen PH, Denny CT, Kim SJ . 2000 Cancer Res. 60: 1536–1540

  • Kelland LR, Burgess L, Steel GG . 1988 Int. J. Radiat. Oncol. Biol. Phys. 14: 1239–1246

  • Kovar H, Aryee DN, Jug G, Henockl C, Schemper M, Delattre O, Thomas G, Gadner H . 1996 Cell Growth Differ. 7: 429–437

  • Leith JT . 1988 Radiat. Res. 114: 186–191

  • Lin PP, Brody RI, Hamelin AC, Bradner JE, Healey JH, Ladanyi M . 1999 Cancer Res. 59: 1428–1432

  • Massagué J, Polyak K . 1995 Curr. Opin. Genet. Dev. 5: 91–96

  • Matsumoto Y, Tanaka K, Nakatani F, Matsunobu T, Matsuda S, Iwamoto Y . 2001 Br. J. Cancer 84: 768–775

  • Ohmori T, Yang JL, Price JO, Arteaga CL . 1998 Exp. Cell. Res. 245: 350–359

  • Ohno T, Ouchida M, Lee L, Gatalica Z, Rao VN, Reddy ES . 1994 Oncogene 9: 3087–3097

  • Ouchida M, Ohno T, Fujimura Y, Rao VN, Reddy ES . 1995 Oncogene 11: 1049–1054

  • Plougastel B, Zucman J, Peter M, Thomas G, Delattre O . 1993 Genomics 18: 609–615

  • Prasad SC, Thraves PJ, Bhatia KG, Smulson ME, Dritschilo A . 1990 Cancer Res. 50: 38–43

  • Rao VN, Ohno T, Prasad DD, Bhattacharya G, Reddy ES . 1993 Oncogene 8: 2167–2173

  • Raynal S, Nocentini S, Croisy A, Lawrence DA, Jullien P . 1997 Int. J. Cancer 72: 356–361

  • Robertson JD, Gogvadze V, Zhivotovsky B, Orrenius S . 2000 J. Biol. Chem. 275: 32438–32443

  • Sementchenko VI, Watson D . 2000 Oncogene 19: 6533–6548

  • Seth A, Giunta S, Franceschil C, Kola I, Venanzoni MC . 1999 Cell Death Differ. 6: 902–907

  • Soldatenkov VA, Albor A, Patel BK, Dreszer R, Dritschilo A, Notario V . 1999a Oncogene 18: 3954–3962

  • Soldatenkov VA, Dritschilo A, Ronai Z, Fuchs SY . 1999b Cancer Res. 59: 5085–5088

  • Sorensen PH, Lessnick SL, Lopez-Terrada D, Liu XF, Triche TJ, Denny CT . 1994 Nat. Genet. 6: 146–151

  • Suzuki H, Romano-Spica V, Papas TS, Bhat NK . 1995 Proc. Natl. Acad. Sci. USA 92: 4442–4446

  • Tanaka K, Iwakuma T, Harimaya K, Sato H, Iwamoto Y . 1997 J. Clin. Invest. 99: 239–247

  • Thraves PJ, Mossman KL, Brennan T, Dritschilo A . 1986 Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 50: 961–972

  • Wasylyk B, Hahn SL, Giovane A . 1993 Eur. J. Biochem. 211: 7–18

  • Wei G, Antonescu CR, de Alava E, Leung D, Huvos AG, Meyers PA, Healey JH, Ladanyi M . 2000 Cancer 89: 793–799

  • Yi H, Fujimura Y, Ouchida M, Prasad DD, Rao VN, Reddy ES . 1997 Oncogene 14: 1259–1268

  • Zucman J, Melot T, Desmaze C, Ghysdael J, Plougastel B, Peter M, Zucker JM, Triche TJ, Sheer D, Turc-Carel C, Ambros P, Combaret V, Lenoir G, Aurias A, Thomas G, Delattre O . 1993 EMBO J. 12: 4481–4487

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Acknowledgements

We are grateful to Dr DK Watson (Medical University of South Carolina, Charleston, SC, USA) for providing ETS1 and EWS/FLI-1 expression plasmids and for discussions and critical suggestions. This work was supported in part by National Institutes of Health grants PO1-CA74175 (to A Dritschilo) and CA64472 (to V Notario) from the National Cancer Institute and by grant DAMD 17-00-1-0019 (to VA Soldatenkov) from the US Department of Defense. Fluorescence microscopy and FACS analyses were performed using the Microscopy/Imaging and the Flow Cytometry/Cell Sorting Shared Resources of the Lombardi Cancer Center, Georgetown University, Washington, D.C, supported in part by US Public Health Service Grant P30-CA51008.

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  1. Department of Radiation Medicine, Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington, 20007, DC, USA

    Viatcheslav A Soldatenkov, Irina N Trofimova, Ana Rouzaut, Frank McDermott, Anatoly Dritschilo & Vicente Notario

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  1. Viatcheslav A Soldatenkov
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Correspondence to Vicente Notario.

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Soldatenkov, V., Trofimova, I., Rouzaut, A. et al. Differential regulation of the response to DNA damage in Ewing's sarcoma cells by ETS1 and EWS/FLI-1. Oncogene 21, 2890–2895 (2002). https://doi.org/10.1038/sj.onc.1205393

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