Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Inhibition of endogenous reverse transcriptase antagonizes human tumor growth

Abstract

Undifferentiated cells and embryos express high levels of endogenous non-telomerase reverse transcriptase (RT) of retroposon/retroviral origin. We previously found that RT inhibitors modulate cell growth and differentiation in several cell lines. We have now sought to establish whether high levels of RT activity are directly linked to cell transformation. To address this possibility, we have employed two different approaches to inhibit RT activity in melanoma and prostate carcinoma cell lines: pharmacological inhibition by two characterized RT inhibitors, nevirapine and efavirenz, and downregulation of expression of RT-encoding LINE-1 elements by RNA interference (RNAi). Both treatments reduced proliferation, induced morphological differentiation and reprogrammed gene expression. These features are reversible upon discontinuation of the anti-RT treatment, suggesting that RT contributes to an epigenetic level of control. Most importantly, inhibition of RT activity in vivo antagonized tumor growth in animal experiments. Moreover, pretreatment with RT inhibitors attenuated the tumorigenic phenotype of prostate carcinoma cells inoculated in nude mice. Based on these data, the endogenous RT can be regarded as an epigenetic regulator of cell differentiation and proliferation and may represent a novel target in cancer therapy.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Brouha B, Schustak J, Badge RM, Lutz-Prigge S, Farley AH, Moran JV and Kazazian Jr HH . (2003). Proc. Natl. Acad. Sci. USA, 100, 5280–5285.

  • Crone TM, Schalles SL, Benedict CM, Pan W, Ren L, Loy SE, Isom H and Clawson GA . (1999). Hepathology, 29, 1114–1123.

  • Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, Niestroj C, Daiber C, Enekel B, Guilliard B, Lauritsch I, Muller E, Pascolo E, Sauter G, Pantic M, Martens UM, Wenz C, Lingner J, Kraut N, Rettig WJ and Schnapp A . (2001). EMBO J., 20, 6958–6968.

  • Deininger PL, Moran JV, Batzer MA and Kazazian HH . (2003). Curr. Opin. Gen. Dev., 13, 651–658.

  • Deragon JM, Sinnett D and Labuda D . (1990). EMBO J., 9, 3363–3368.

  • Di Marzo Veronese F, Copeland TD, De Vico AL, Rahman R, Oroszlan S, Gallo RC and Sarngadharan MG . (1986). Science, 231, 1289–1291.

  • Egger G, Liang G, Aparicio A and Jones PA . (2004). Nature, 429, 457–463.

  • Ergun S, Buschmann C, Heukeshoven J, Dammann K, Schnieders F, Lauke H, Chalajour F, Nerbil K, Stratling WH and Schumann GG . (2004). J. Biol. Chem., 279, 27753–27763.

  • Friedlander A and Patarca R . (1999). Crit. Rev. Oncogenesis, 10, 129–159.

  • Giordano R, Magnano AR, Zaccagnini G, Pittoggi C, Moscufo N, Lorenzini R and Spadafora C . (2000). J. Cell Biol., 148, 1107–1113.

  • Hagan CR and Rudin CM . (2002). Am. J. Pharmacogenomics., 2, 25–36.

  • Hagan CR, Sheffield RF and Rudin CM . (2003). Nat. Genet., 35, 219–220.

  • Hsu MY, Meier FE, Nesbit M, Hsu JY, Van Belle P, Elder DE and Herlyn M . (2000). Am. J. Pathol., 156, 1515–1525.

  • Khan AS, Muller J and Sears JF . (2001). Virus Res., 79, 39–45.

  • Kiessling AA, Crowell R and Fox C . (1989). Proc. Acad. Natl. Sci. USA, 86, 5109–5113.

  • Kuo KW, Sheu HM, Huang YS and Leung WC . (1998). Biochem. Biophys. Res. Commun., 253, 566–570.

  • Li L, Connelly MC, Wetmore C, Curran T and Morgan JI . (2003). Cancer Res., 63, 2733–2736.

  • Li TH and Schmid CW . (2001). Gene, 276, 135–141.

  • Lilja H . (2003). Urology, 62 (Suppl 1), 27–33.

  • Linja MJ, Savinainem KJ, Saramaki OR, Tammela TL, Vessella RL and Visakorpi T . (2001). Cancer Res., 61, 3550–3555.

  • Lotem J and Sachs L . (2002). Cancer Biol., 12, 339–346.

  • Mangiacasale R, Pittoggi C, Sciamanna I, Careddu A, Mattei E, Lorenzini R, Travaglini L, Landriscina M, Barone C, Nervi C, Lavia P and Spadafora C . (2003). Oncogene, 22, 2750–2761.

  • Martin SL . (1991). Mol. Cell. Biol., 11, 4804–4807.

  • Martin SL and Branciforte D . (1993). Mol. Cell. Biol., 13, 5383–5392.

  • Melino G, Sinibaldi Vallebona P, D'Atri S, Annichiarico-Petruzzelli M, Rasi G, Catani MV, Tartaglia MI, Vernole P, Spagnoli LG, Finazzi-Agrò A and Garaci E . (1993). Clin. Chem. Enzyme Comms., 6, 105–119.

  • Mwenda JM . (1993). Cell. Mol. Biol., 39, 317–328.

  • Osborne CS, Chalakova L, Brown KE, Carter D, Horton A, Debrand E, Goyenechea B, Mitchell JA, Lopes S, Reik W and Fraser P . (2004). Nat. Genet., 36, 1065–1071.

  • Ostertag EM and Kazazian Jr HH . (2001). Annu. Rev. Genet., 35, 501–538.

  • Packer AI, Manova K and Bacharova RF . (1993). Dev. Biol., 157, 281–283.

  • Pittoggi C, Sciamanna I, Mattei E, Beraldi R, Lobascio AM, Mai A, Quaglia MG, Lorenzini R and Spadafora C . (2003). Mol. Reprod. Dev., 66, 225–236.

  • Pyra H, Boni J and Schupbach J . (1994). Proc. Natl. Acad. Sci. USA, 91, 1544–1548.

  • Portsmouth S, Stebbing J, Gill J, Mandalia S, Bower M, Nelson M, Bower M and Gazzard B . (2003). AIDS, 17, F17–F22.

  • Poznanski AA and Calarco PG . (1991). Dev. Biol., 143, 271–281.

  • Ren J, Nichols C, Bird L, Chamberlain P, Weaver K, Short S, Stuart DI and Stammers DK . (2001). J. Mol. Biol., 312, 795–805.

  • Sauane M, Gopalkrishnan RV, Sarkar D, Su ZZ, Lebedeva IV, Dent P, Pestka S and Fisher PB . (2003). Cyt. Growth Factor Rev., 14, 35–51.

  • Sauter ER, Yeo UC, Von Stemm A, Zhu W, Litwin S, Tichansky DS, Pistritto G, Nesbit M, Pinkel D, Herl M and Bastian BC . (2002). Cancer Res., 62, 3200–3206.

  • Schramke V and Allshire R . (2003). Science, 301, 1069–1074.

  • Tirelli U and Bernardi D . (2001). Eur. J. Cancer., 37, 1320–1324.

  • Umekita Y, Hiipakka RA, Koknotis JM and Shutsung L . (1996). Proc. Natl. Acad. Sci. USA, 93, 11802–11807.

  • Utikal J, Leiter U, Udart M, Kaskel P, Peter RU and Krahn GM . (2002). Cancer Invest., 20, 914–921.

Download references

Acknowledgements

We are indebted with Dr Gerald Schumann for kindly providing the antibody against LINE1-encoded RT. We are also grateful to Dr A Mai for drug purification and to Drs R Mangiacasale and S Rutella for cell cycle analysis. This work was supported by Istituto Superiore di Sanità (Grant C3H3 ‘Role of endogenous Reverse Transcriptase in tumor growth and embryo differentiation’).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Corrado Spadafora.

Additional information

Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sciamanna, I., Landriscina, M., Pittoggi, C. et al. Inhibition of endogenous reverse transcriptase antagonizes human tumor growth. Oncogene 24, 3923–3931 (2005). https://doi.org/10.1038/sj.onc.1208562

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208562

Keywords

This article is cited by

Search

Quick links