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RETRACTED ARTICLE: RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine

Oncogene volume 23, pages 1539–1548 (2004)Cite this article

This article was retracted on 16 February 2023

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Abstract

Ribonucleotide reductase is emerging as an important determinant of gemcitabine chemoresistance in human cancers. Activity of this enzyme, which catalyses conversion of ribonucleotide 5′-diphosphates to their 2′-deoxynucleotides, is modulated by levels of its M2 subunit (RRM2). Here we show that RRM2 overexpression is associated with gemcitabine chemoresistance in pancreatic adenocarcinoma cells, and that suppression of RRM2 expression using RNA interference mediated by small interfering RNA (siRNA) enhances gemcitabine-induced cytotoxicity in vitro. We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma. Synergism between RRM2 siRNA and gemcitabine results in markedly suppressed tumor growth, increased tumor apoptosis and inhibition of metastasis. Our findings confirm the importance of RRM2 in pancreatic adenocarcinoma gemcitabine chemoresistance. This is the first demonstration that systemic delivery of siRNA-based therapy can enhance the efficacy of an anticancer nucleoside analog.

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References

  • Adjei AA, Dy GK, Erlichman C, Reid JM, Sloan JA, Pitot HC, Alberts SR, Goldberg RM, Hanson LJ, Atherton PJ, Watanabe T, Geary RS, Holmlund J and Dorr FA . (2003). Clin. Cancer Res., 9, 115–123.

  • Aoki Y, Cioca DP, Oidaira H, Kamiya J and Kiyosawa K . (2003). Clin. Exp. Pharmacol. Physiol., 30, 96–102.

  • Arlt A, Gehrz A, Muerkoster S, Vorndamm J, Kruse ML, Folsch UR and Schafer H . (2003). Oncogene, 22, 3243–3251.

  • Bergman AM, Pinedo HM and Peters GJ . (2002). Drug Resist. Updat., 5, 19–33.

  • Bertrand JR, Pottier M, Vekris A, Opolon P, Maksimenko A and Malvy C . (2002). Biochem. Biophys. Res. Commun., 296, 1000–1004.

  • Brummelkamp TR, Bernards R and Agami R . (2002a). Science, 296, 550–553.

  • Brummelkamp TR, Bernards R and Agami R . (2002b). Cancer Cell, 2, 243–247.

  • Burris III HA, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD and Von Hoff DD . (1997). J. Clin. Oncol., 15, 2403–2413.

  • Calzado MA, Macho A, Lucena C and Munoz E . (2000). Clin. Exp. Immunol., 120, 317–323.

  • Cory JG . (1997). Purine and pyrimidine nucleotide metabolism. Devlin T (ed). Biochemistry with Clinical Correlations. Wiley-Liss: New York, pp. 489–523.

    Google Scholar 

  • Editorial (2003). Nat. Cell Biol., 5, 489–490.

  • Endicott JA and Ling V. . (1989). Annu. Rev. Biochem., 58, 137–171.

  • Eriksson S and Martin Jr DW . (1981). J. Biol. Chem., 256, 9436–9440.

  • Fan H, Villegas C and Wright JA . (1996). Proc. Natl. Acad. Sci. USA, 93, 14036–14040.

  • Filleur S, Courtin A, Ait-Si-Ali S, Guglielmi J, Merle C, Harel-Bellan A, Clezardin P and Cabon F . (2003). Cancer Res., 63, 3919–3922.

  • Fujioka S, Sclabas GM, Schmidt C, Frederick WA, Dong QG, Abbruzzese JL, Evans DB, Baker C and Chiao PJ . (2003). Clin. Cancer Res., 9, 346–354.

  • Goan YG, Zhou B, Hu E, Mi S and Yen Y . (1999). Cancer Res., 59, 4204–4207.

  • Gorelik E, Kim M, Duty L, Henion T and Galili U . (1993). Clin. Exp. Metastasis, 11, 439–452.

  • Grant CE, Valdimarsson G, Hipfner DR, Almquist KC, Cole SP and Deeley RG . (1994). Cancer Res., 54, 357–361.

  • Guittet O, Hakansson P, Voevodskaya N, Fridd S, Graslund A, Arakawa H, Nakamura Y and Thelander L . (2001). J. Biol. Chem., 276, 40647–40651.

  • Heinemann V, Hertel LW, Grindey GB and Plunkett W . (1988). Cancer Res., 48, 4024–4031.

  • Inayat MS, Chendil D, Mohiuddin M, Elford HL, Gallicchio VS and Ahmed MM . (2002). Cancer Biol. Ther., 1, 539–545.

  • Jemal A, Murray T, Samuels A, Ghafoor A, Ward E and Thun MJ . (2003). CA Cancer J. Clin., 53, 5–26.

  • Jong AY, Yu K, Zhou B, Frgala T, Reynolds CP and Yen Y . (1998). J. Biomed. Sci., 5, 62–68.

  • Jung CP, Motwani MV and Schwartz GK . (2001). Clin. Cancer Res., 7, 2527–2536.

  • Kelley JR, Fraser MM, Schweinfest CW, Vournakis JN, Watson DK and Cole DJ . (2001). Surgery, 130, 280–288.

  • Kunsch C, Ruben SM and Rosen CA . (1992). Mol. Cell. Biol., 12, 4412–4421.

  • Lee Y, Vassilakos A, Feng N, Lam V, Xie H, Wang M, Jin H, Xiong K, Liu C, Wright J and Young A . (2003). Cancer Res., 63, 2802–2811.

  • Li K, Lin SY, Brunicardi FC and Seu P . (2003). Cancer Res., 63, 3593–3597.

  • McClarty GA, Chan AK, Engstrom Y, Wright JA and Thelander L . (1987). Biochemistry, 26, 8004–8011.

  • Monteith DK, Henry SP, Howard RB, Flournoy S, Levin AA, Bennett CF and Crooke ST . (1997). Anticancer Drug Des., 12, 421–432.

  • Muerkoster S, Arlt A, Witt M, Gehrz A, Haye S, March C, Grohmann F, Wegehenkel K, Kalthoff H, Folsch UR and Schafer H . (2003). Int. J. Cancer, 104, 469–476.

  • Nieth C, Priebsch A, Stege A and Lage H . (2003). FEBS Lett., 545, 144–150.

  • Pavloff N, Rivard D, Masson S, Shen SH and Mes-Masson AM . (1992). DNA Seq., 2, 227–234.

  • Pessara U and Koch N . (1990). Mol. Cell. Biol., 10, 4146–4154.

  • Plunkett W, Huang P, Searcy CE and Gandhi V . (1996). Semin. Oncol., 23, 3–15.

  • Plunkett W, Huang P, Xu YZ, Heinemann V, Grunewald R and Gandhi V . (1995). Semin. Oncol., 22, 3–10.

  • Raitano AB, Scuderi P and Korc M . (1990). Pancreas, 5, 267–277.

  • Reichard P . (1978). Fed. Proc., 37, 9–14.

  • Reichard P . (1985). Basic Life Sci., 31, 33–45.

  • Sclabas GM, Fujioka S, Schmidt C, Evans DB and Chiao PJ . (2003). Int. J. Gastrointest. Cancer, 33, 15–26.

  • Shen Z, Peedikayil J, Olson GK, Siebert PD and Fang Y . (2002). Biotechniques, May 32 (5), 1168, 1170-2, 1174 passim.

  • Sun FX, Tohgo A, Bouvet M, Yagi S, Nassirpour R, Moossa AR and Hoffman RM . (2003). Cancer Res., 63, 80–85.

  • Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y and Nakamura Y . (2000). Nature, 404, 42–49.

  • Thelander L and Berg P . (1986). Mol. Cell. Biol., 6, 3433–3442.

  • Thelander M, Graslund A and Thelander L . (1985). J. Biol. Chem., 260, 2737–2741.

  • Wright JA, Alam TG, McClarty GA, Tagger AY and Thelander L . (1987). Somat. Cell Mol. Genet., 13, 155–165.

  • Zhou B, Mo X, Liu X, Qiu W and Yen Y . (2001). Cytogenet. Cell Genet., 95, 34–42.

  • Zhou BS, Hsu NY, Pan BC, Doroshow JH and Yen Y . (1995). Cancer Res., 55, 1328–1333.

  • Zhou BS, Tsai P, Ker R, Tsai J, Ho R, Yu J, Shih J and Yen Y . (1998). Clin. Exp. Metastas., 16, 43–49.

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Acknowledgements

We gratefully acknowledge the technical assistance of Jan Rounds. This work was supported by The National Pancreas Foundation and departmental funds from the Department of Surgery, Brigham and Women's Hospital.

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Authors and Affiliations

  1. Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, USA

    Mark S Duxbury, Hiromichi Ito, Michael J Zinner, Stanley W Ashley & Edward E Whang

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  1. Mark S Duxbury
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  2. Hiromichi Ito
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  3. Michael J Zinner
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  5. Edward E Whang
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Correspondence to Edward E Whang.

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This article has been retracted. Please see the retraction notice for more detail:https://doi.org/10.1038/s41388-023-02625-6

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Duxbury, M., Ito, H., Zinner, M. et al. RETRACTED ARTICLE: RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Oncogene 23, 1539–1548 (2004). https://doi.org/10.1038/sj.onc.1207272

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