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:

B-RAF and PI-3 kinase signaling protect melanoma cells from anoikis

Oncogene volumeĀ 25,Ā pages 4848ā€“4856 (2006)Cite this article

Abstract

A hallmark feature of cancer is resistance to anoikis, apoptosis induced when cells either lose contact with or encounter an inappropriate extracellular matrix. Melanoma is inherently associated with a high degree of resistance to apoptosis. Mutations in B-RAF are prevalent in melanoma and promote constitutive MEKā€“ERK1/2 signaling and cell transformation. Acquisition of B-RAF mutations correlates with vertical phase growth when melanoma cells invade into the dermis, a collagen-rich environment that also contains fibronectin matrix. In addition, alterations in phosphoinositide-3 kinase (PI-3 kinase) signaling that lead to activation of AKT are detected in advanced melanomas. Here we show that knockdown of B-RAF expression by siRNA or pharmacological inhibition of MEK rendered melanoma cells susceptible to anoikis. Furthermore, adhesion to fibronectin but not collagen protected melanoma cells from anoikis through a PI-3 kinase-dependent pathway. Therefore, melanoma cells require either B-RAF or PI-3 kinase activation for protection from anoikis. Notably, AKT signaling in melanoma cells is substrate specific. These findings demonstrate that melanoma cells utilize multiple signaling pathways to provide resistance to apoptosis.

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
Figure 6
Figure 7

Similar content being viewed by others

Abbreviations

Bad:

Bcl-XL/Bcl-2-associated death promoter

Bim:

Bcl-2 interacting mediator of cell death

FAK:

focal adhesion kinase

IAP:

inhibitor of apoptosis protein

NHEM:

normal human epidermal melanocyte

PI-3 kinase:

phosphoinositide-3 kinase

PTEN:

phosphatase and tensin homolog

siRNA:

small interfering RNA

TUNEL:

TdT-mediated dUTP nick-end labeling

References

  • Alanko T, Rosenberg M, Saksela O . (1999). J Invest Dermatol 113: 111ā€“116.

  • Alanko T, Saksela O . (2000). J Invest Dermatol 115: 286ā€“291.

  • Alonso SR, Ortiz P, Pollan M, Perez-Gomez B, Sanchez L, Acuna MJ et al. (2004). Am J Pathol 164: 193ā€“203.

  • Bataille V . (2003). Eur J Cancer 39: 1341ā€“1347.

  • Bhatt KV, Spofford LS, Aram G, McMullen M, Pumiglia K, Aplin AE . (2005). Oncogene 12: 3459ā€“3471.

  • Biswas SCA, Greene LA . (2002). J Biol Chem 277: 49511ā€“49516.

  • Bouillet P, Cory S, Zhang LC, Strasser A, Adams JM . (2001). Dev Cell 1: 645ā€“653.

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Cell 96: 857ā€“868.

  • Calipel A, Lefevre G, Pouponnot C, Mouriaux F, Eychene A, Mascarelli F . (2003). J Biol Chem 278: 42409ā€“42418.

  • Conner SR, Scott G, Aplin AE . (2003). J Biol Chem 278: 34548ā€“34554.

  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA . (1995). Nature 378: 785ā€“789.

  • Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al. (1997). Cell 91: 231ā€“241.

  • Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB et al. (2000). Mol Cell 6: 41ā€“51.

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

  • Davies MA, Lu Y, Sano T, Fang X, Tang P, LaPushin R et al. (1998). Cancer Res 58: 5285ā€“5290.

  • del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G . (1997). Science 278: 687ā€“689.

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

  • Eisenmann KM, VanBrocklin MW, Staffend NA, Kitchen SM, Koo H-M . (2003). Cancer Res 63: 8330ā€“8337.

  • Erhardt P, Schremser EJ, Cooper GM . (1999). Mol Cell Biol 19: 5308ā€“5315.

  • Frisch SM, Francis H . (1994). J Cell Biol 124: 619ā€“626.

  • Fukazawa H, Noguchi K, Murakami Y, Uehara Y . (2002). Mol Cancer Ther 1: 303ā€“309.

  • Gaggioli C, Deckert M, Robert G, Abbe P, Batoz M, Ehrengruber MU et al. (2005). Oncogene 24: 1423ā€“1433.

  • Giancotti FG, Ruoslahti E . (1999). Science 285: 1028ā€“1032.

  • Gill M, Celebi JT . (2005). J Am Acad Dermatol 53: 108ā€“114.

  • Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J . (1997). Cancer Res 57: 3660ā€“3663.

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

  • Howe AK, Aplin AE, Juliano RL . (2002). Curr Opin Genet Dev 12: 30ā€“35.

  • Huser M, Luckett J, Chiloeches A, Mercer K, Iwobi M, Giblett S et al. (2001). EMBO J 20: 1940ā€“1951.

  • Jost M, Huggett TM, Kari C, Rodeck U . (2001). Mol Biol Cell 12: 1519ā€“1527.

  • Kane LP, Shapiro VS, Stokoe D, Weiss A . (1999). Curr Biol 9: 601ā€“604.

  • Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F et al. (2004). Oncogene 23: 6292ā€“6298.

  • Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J . (1997). EMBO J 16: 2783ā€“2793.

  • Koh HK . (1991). N Engl J Med 325: 171ā€“182.

  • Le Gall M, Chambard JC, Breittmayer JP, Grall D, Pouyssegur J, Van Obberghen-Schilling E . (2000). Mol Biol Cell 11: 1103ā€“1112.

  • Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ . (2003). J Biol Chem 278: 18811ā€“18816.

  • Marshman E, Green KA, Flint DJ, White A, Streuli CH, Westwood M . (2003). J Cell Sci 116: 675ā€“682.

  • Mayo LD, Donner DB . (2001). Proc Natl Acad Sci USA 98: 11598ā€“11603.

  • O'Neill E, Rushworth L, Baccarini M, Kolch W . (2004). Science 306: 2267ā€“2270.

  • Pap M, Cooper GM . (1998). J Biol Chem 273: 19929ā€“19932.

  • Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM et al. (2003). Nat Genet 33: 19ā€“20.

  • Qi X-J, Wildey GM, Howe PH . (2006). J Biol Chem 281: 813ā€“823.

  • Reginato MJ, Mills KR, Paulus JK, Lynch DK, Sgroi DC, Debnath J et al. (2003). Nat Cell Biol 6: 6.

  • Satyamoorthy K, Li G, Gerrero MR, Brose MS, Volpe P, Weber BL et al. (2003). Cancer Res 63: 756ā€“759.

  • Schulze A, Lehmann K, Jefferies HBJ, McMahon M, Downward J . (2001). Genes Dev 15: 981ā€“994.

  • Schulze A, Nicke B, Warne PH, Tomlinson S, Downward J . (2004). Mol Biol Cell 15: 3450ā€“3463.

  • Scott G, Cassidy L, Busacco A . (1997). J Invest Dermatol 108: 147ā€“153.

  • She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N . (2005). Cancer Cell 8: 287ā€“297.

  • Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP . (2003). Cancer Res 63: 2881ā€“2890.

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

  • Sumimoto H, Miyagishi M, Miyoshi H, Yamagata S, Shimizu A, Taira K et al. (2004). Oncogene 23: 6031ā€“6039.

  • Tsao H, Zhang X, Benoit E, Haluska FG . (1998). Oncogene 16: 3397ā€“3402.

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

  • Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF . (1999). Mol Cell Biol 19: 6195ā€“6206.

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

Download references

Acknowledgements

We are grateful to Drs Michael DiPersio and Jihe Zhao for helpful discussions and Dr Mark Preissler in the flow cytometry core facility at AMC for skilled technical assistance. We thank The Birth Center at Albany Medical Center and AndrƩs Melendez for reagents and Dr Meenhard Herlyn (Wistar Institute) for the melanoma cell lines. This work was supported in part by NIH Grant GM067893.

Author information

Authors and Affiliations

  1. Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY, USA

    K Boisvert-AdamoĀ &Ā A E Aplin

Authors
  1. K Boisvert-Adamo
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

  2. A E Aplin
    View author publications

    You can also search for this author in PubMedĀ Google Scholar

Corresponding author

Correspondence to A E Aplin.

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

Boisvert-Adamo, K., Aplin, A. B-RAF and PI-3 kinase signaling protect melanoma cells from anoikis. Oncogene 25, 4848ā€“4856 (2006). https://doi.org/10.1038/sj.onc.1209493

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1209493

Keywords

This article is cited by

Search

Advanced search

Quick links