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 Article
  • Published:

Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs

Oncogene volume 25, pages 6574–6581 (2006)Cite this article

Abstract

The type 1 insulin-like growth factor receptor (IGF1R) is overexpressed by malignant melanomas compared with benign naevi, and mediates proliferation, motility and protection from apoptosis. However, the utility of IGF1R targeting as anti-cancer therapy may be limited by activating mutations in downstream signaling intermediates. We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss. The current study investigated effects of IGF1R targeting in cells harboring activating RAS-RAF mutations, found in 70–80% of human melanomas. We assembled a panel of eight human melanoma cell lines: two expressing wild-type (WT) B-RAF and N-RAS, two with activating N-RAS mutations and four harboring V600E B-RAF. We also generated isogenic cell populations overexpressing WT or V600E B-RAF. Cells expressing V600E B-RAF were relatively resistant to apoptosis. However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and ∼two-fold sensitization to cisplatin and temozolomide. These effects were independent of mutation status and were associated with reduced activation of Akt and also, unexpectedly, of ERKs. These results support development of IGF1R targeting as therapy for melanoma, regardless of the presence of activating mutations in the RAS-RAF pathway.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Baserga R, Hongo A, Rubini M, Prisco M, Valentinis B . (1997). Biochim Biophys Acta 1332: F105–F126.

  • Benini S, Manara MC, Cerisano V, Perdichizzi S, Strammiello R, Serra M et al. (2004). Int J Cancer 108: 358–366.

  • Bohula EA, Playford MP, Macaulay VM . (2003a). Anticancer Drugs 14: 669–682.

  • Bohula EA, Salisbury AJ, Sohail M, Playford MP, Riedemann J, Southern EM et al. (2003b). J Biol Chem 278: 15991–15997.

  • Bos JL . (1989). Cancer Res 49: 4682–4689.

  • Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R et al. (2002). Cancer Res 62: 6997–7000.

  • Camp ER, Summy J, Bauer TW, Liu W, Gallick GE, Ellis LM . (2005). Clin Cancer Res 11: 397–405.

  • Danson S, Lorigan P, Arance A, Clamp A, Ranson M, Hodgetts J et al. (2003). J Clin Oncol 21: 2551–2557.

  • Danson SJ, Middleton MR . (2001). Expert Rev Anticancer Ther 1: 13–19.

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S et al. (2002). Nature 417: 949–954.

  • Dong J, Phelps RG, Qiao R, Yao S, Benard O, Ronai Z et al. (2003). Cancer Res 63: 3883–3885.

  • Dunn SE, Hardman RA, Kari FW, Barrett JC . (1997). Cancer Res 57: 2687–2693.

  • Garber K . (2005). J Natl Cancer Inst 97: 790–792.

  • Geier A, Weiss C, Beery R, more A . (1995). J Cell Physiol 163: 570–576.

  • Gooch JL, Berg CLVD, Yee D . (1999). Breast Cancer Res Treat 56: 1–10.

  • Gorden A, Osman I, Gai W, He D, Huang W, Davidson A et al. (2003). Cancer Res 63: 3955–3957.

  • Hagemann C, Rapp UR . (1999). Exp Cell Res 253: 34–46.

  • Hellawell GO, Ferguson DJ, Brewster SF, Macaulay VM . (2003). BJU Int 91: 271–277.

  • Hingorani SR, Jacobetz MA, Robertson GP, Herlyn M, Tuveson DA . (2003). Cancer Res 63: 5198–5202.

  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A et al. (2005). CA Cancer J Clin 55: 10–30.

  • Kanter-Lewensohn L, Dricu A, Girnita L, Wejde J, Larsson O . (2000). Growth Factors 17: 193–202.

  • Kumar R, Angelini S, Czene K, Sauroja I, Hahka-Kemppinen M, Pyrhonen S et al. (2003). Clin Cancer Res 9: 3362–3368.

  • LeRoith D . (2000). Endocrinology 141: 1287–1288.

  • Macaluso M, Russo G, Cinti C, Bazan V, Gebbia N, Russo A . (2002). J Cell Physiol 192: 125–130.

  • Macaulay VM, Salisbury AJ, Bohula EA, Playford MP, Smorodinsky NI, Shiloh Y . (2001). Oncogene 20: 4029–4040.

  • Marshall CJ . (1994). Curr Opin Genet Dev 4: 82–89.

  • McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR . (1999). Cancer Res 59: 4291–4296.

  • Min Y, Adachi Y, Yamamoto H, more a . (2003). Cancer Res 63: 6432–6441.

  • Moelling K, Schad K, Bosse M, Zimmermann S, Schweneker M . (2002). J Biol Chem 277: 31099–31106.

  • O'Connor R . (2003). Horm Metab Res 35: 771–777.

  • Park S, Yeung ML, Beach S, Shields JM, Yeung KC . (2005). Oncogene 24: 3535–3540.

  • Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G et al. (1999). Mol Cell Biol 19: 7203–7215.

  • Resnicoff M, Coppola D, Sell C, Rubin R, Ferrone S, Baserga R . (1994). Cancer Res 54: 4848–4850.

  • Rochester MA, Riedemann J, Hellawell GO, Brewster SF, Macaulay VM . (2005). Cancer Gene Ther 12: 90–100.

  • Sato S, Fujita N, Tsuruo T . (2004). J Biol Chem 279: 33759–33767.

  • Sell C, Baserga R, Rubin R . (1995). Cancer Res 55: 303–306.

  • Sharma A, Trivedi NR, Zimmerman MA, Tuveson DA, Smith CD, Roberson GP . (2005). Cancer Res 65: 2412–2421.

  • Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A et al. (2005). Nature 439: 358–362.

  • Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW et al. (2004). Cancer Res 64: 7002–7010.

  • Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM et al. (2004). Cell 116: 855–867.

  • Wang D, Lippard SJ . (2005). Nat Rev Drug Discov 4: 307–320.

  • Wellbrock C, Karasarides M, Marais R . (2004a). Nat Rev Mol Cell Biol 5: 875–885.

  • Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D et al. (2004b). Cancer Res 64: 2338–2342.

  • Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME . (1995). Science 270: 1326–1331.

  • Xiao D, Choi S, Lee YJ, Singh SV . (2005). Mol Carcinog 43: 130–140.

Download references

Acknowledgements

We are grateful to Richard Marais for providing the B-RAF constructs and to Ian Hickson and Stephan Feller for comments on this paper. This project was supported by Cancer Research UK and by a Rhodes Scholarship to EAB.

Author information

Authors and Affiliations

  1. IGF Group, Cancer Research UK Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK

    A H Yeh, E A Bohula & V M Macaulay

Authors
  1. A H Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E A Bohula
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. V M Macaulay
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V M Macaulay.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yeh, A., Bohula, E. & Macaulay, V. Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs. Oncogene 25, 6574–6581 (2006). https://doi.org/10.1038/sj.onc.1209674

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209674

Keywords

This article is cited by

Search

Advanced search

Quick links