Abstract
Using a proteomic approach to screen for new growth factors released by melanoma cells, we identified follistatin as a major heparin-binding factor in medium conditioned by the Bowes melanoma cell line. Since follistatin is primarily studied in relation to its neutralization of activin, a member of the transforming growth factor-β family of ligands, the expression and function of this receptor system was investigated in a panel of melanoma cell lines and melanocytes. All cell lines expressed activin receptors and showed phosphorylation of Smad signal transduction molecules upon treatment with activin. Secretion of follistatin, either native or after retroviral transduction, efficiently prevented Smad activation or activation of an activin-responsive luciferase reporter construct. In melanocytes, activin treatment led to growth inhibition and induction of apoptosis. These effects were counteracted by cotreatment with follistatin. In summary, we characterized the activin–activin receptor system in melanocytes and melanoma cell lines and found that secretion of follistatin by melanoma cells may represent an effective way to circumvent activin's negative regulatory effects.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Abbreviations
- CM:
-
conditioned medium
- EGFP:
-
enhanced green fluorescence protein
- FS:
-
follistatin
- IRES:
-
internal ribosomal entry site
- LIE:
-
LZRS-IRES-EGFP
- PMA:
-
phorbol 12-myristate 13-acetate
- TGF-β:
-
transforming growth factor-β
References
Alanko T and Saksela O . (2000). J. Invest. Dermatol., 115, 286–291.
Ball EMA and Risbridger GP . (2001). Dev. Biol., 238, 1–12.
Bartkova J, Lukas J, Guldberg P, Alsner J, Kirkin AF, Zeuthen J and Bartek J . (1996). Cancer Res., 56, 5475–5483.
Beer H-D, Gassmann MG, Munz B, Steiling H, Engelhardt F, Bleuel K and Werner S . (2000). J. Investig. Dermatol. Symp. Proc., 5, 34–39.
Berking C, Takemoto R, Schaider H, Showe L, Satyamoorthy K, Robbins P and Herlyn M . (2001). Cancer Res., 61, 8306–8316.
Blume-Jensen P and Hunter T . (2001). Nature, 411, 355–365.
Chen Y-G, Lui HM, Lin S-L, Lee JM and Ying SY . (2002). Exp. Biol. Med., 227, 75–87.
Cho SH, Yao Z, Wang S-W, Alban RF, Barbers RG, French SW and Oh CK . (2003). J. Immunol., 170, 4045–4052.
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JWC, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR and Futreal PA . (2002). Nature, 417, 949–954.
Delbaere A, Sidis Y and Schneyer AL . (1999). Endocrinology, 140, 2463–2470.
Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S and Gauthier J-M . (1998). EMBO J., 17, 3091–3100.
Devreese B, Janssen KPC, Vanrobaeys F, Van Herp F, Martens GJM and Van Beeumen J . (2002). J. Chromatogr. A., 976, 113–121.
de Winter JP, ten Dijke P, de Vries CJM, van Achterberg TAE, Sugino H, de Waele P, Huylebroeck D, Verschueren K and van den Eijnden-van Raaij AJM . (1996). Mol. Cell. Endocrinol., 116, 105–114.
Esch FS, Shimasaki S, Mercado M, Cooksey K, Ling N, Ying S, Ueno N and Guillemin R . (1987). Mol. Endocrinol., 1, 849–855.
Gray PC, Harrison CA and Vale W . (2003). Proc. Natl. Acad. Sci. USA, 100, 5193–5198.
Gullick WJ . (2001). Breast Cancer Res., 3, 390–394.
Gumienny TL and Padgett RW . (2002). Trends Endocrinol. Metab., 13, 295–299.
Hager JW . (2002). Rapid Commun. Mass Spectrom., 16, 512–526.
Hashimoto O, Nakamura T, Shoji H, Shimasaki S, Hayashi Y and Sugino H . (1997). J. Biol. Chem., 272, 13835–13842.
Hempen PM, Zhang L, Bansal RK, Iacobuzio-Donahue CA, Murphy KM, Maitra A, Vogelstein B, Whitehead RH, Markowitz SD, Willson JKV, Yeo CJ, Hruban RH and Kern SE . (2003). Cancer Res., 63, 994–999.
Innis CA and Hyvönen M . (2003). J. Biol. Chem., 278, 39969–39977.
Inouye S, Guo Y, DePaolo L, Shimonaka M, Ling N and Shimasaki S . (1991). Endocrinology, 129, 815–822.
Knight PG . (1996). Front. Neuroendocrinol., 17, 476–509.
Lázár-Molnár E, Hegyesi H, Tóth S and Falus A . (2000). Cytokine, 12, 547–554.
Ling N, Ying S-Y, Ueno N, Shimasaki S, Esch F, Hotta M and Guillemin R . (1986). Nature, 321, 779–782.
Liu QY, Niranjan B, Gomes P, Gomm JJ, Davies D, Coombes RC and Buluwela L . (1996). Cancer Res., 56, 1155–1163.
Luisi S, Florio P, Reis FM and Petraglia F . (2001). Eur. J. Endocrinol., 145, 225–236.
Massagué J and Chen Y-G . (2000). Genes Dev., 14, 627–644.
Meier F, Satyamoorthy K, Nesbit M, Hsu M-Y, Schittek B, Garbe C and Herlyn M . (1998). Front. Biosci., 3, D1005–D1010.
Michel U and Farnworth P . (1992). Endocrinology, 130, 3684–3693.
Munz B, Smola H, Engelhardt F, Bleuel K, Brauchle M, Lein I, Evans LW, Huylebroeck D, Balling R and Werner S . (1999). EMBO J., 18, 5205–5215.
Nakamura T, Takio K, Eto Y, Shibai H, Titani K and Sugino H . (1990). Science, 247, 836–838.
Risbridger GP, Schmitt JF and Robertson DM . (2001). Endocr. Rev., 22, 836–858.
Robertson DM, Klein R, de Vos FL, McLachlan RI, Wettenhall REH, Hearn MTW, Burger HG and de Kretser DM . (1987). Biochem. Biophys. Res. Commun., 149, 744–749.
Rodeck U, Bossler A, Graeven U, Fox FE, Nowell PC, Knabbe C and Kari C . (1994). Cancer Res., 54, 575–581.
Rodeck U, Nishiyama T and Mauviel A . (1999). Cancer Res., 59, 547–550.
Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E and Polakis P . (1997). Science, 275, 1790–1792.
Sandra K, Devreese B, Stals I, Claeyssens M and Van Beeumen J . (2003). J. Am. Soc. Mass Spectrom., 15, 413–423.
Schneyer AL, Hall HA, Lambert-Messerlian G, Wang QF, Sluss P and Crowley Jr WF . (1996). Endocrinology, 137, 240–247.
Schneyer AL, Rzucidlo DA, Sluss PM and Crowley Jr WF . (1994). Endocrinology, 135, 667–674.
Shellman YG, Chapman JT, Fujita M, Norris DA and Maxwell IH . (2000). J. Invest. Dermatol., 114, 1200–1204.
Shi Y and Massagué J . (2003). Cell, 113, 685–700.
Shimasaki S, Koga M, Esch F, Cooksey K, Mercado M, Koba A, Ueno N, Ying S-Y, Ling N and Guillemin R . (1988). Proc. Natl. Acad. Sci. USA, 85, 4218–4222.
Sidis Y, Schneyer AL, Sluss PM, Johnson LN and Keutmann HT . (2001). J. Biol. Chem., 276, 17718–17726.
Sidis Y, Tortoriello DV, Holmes WE, Pan Y, Keutmann HT and Schneyer AL . (2002). Endocrinology, 143, 1613–1624.
Stove C, Stove V, Derycke L, Van Marck V, Mareel M and Bracke M . (2003a). J. Invest. Dermatol., 121, 802–812.
Stove V, Naessens E, Stove C, Swigut T, Plum J and Verhasselt B . (2003b). Blood, 102, 2925–2932.
Tano M, Minegishi T, Nakamura K, Nakamura M, Karino S, Miyamoto K and Ibuki Y . (1995). Mol. Cell. Endocrinol., 109, 167–174.
Tuveson DA, Weber BL and Herlyn M . (2003). Cancer Cell, 4, 95–98.
Ueno N, Ling N, Ying S-Y, Esch F, Shimasaki S and Guillemin R . (1987). Proc. Natl. Acad. Sci. USA, 84, 8282–8286.
Vale W, Rivier J, Vaughan J, McClintock R, Corrigan A, Woo W, Karr D and Spiess J . (1986). Nature, 321, 776–779.
Wang Q, Keutmann HT, Schneyer AL and Sluss PM . (2000). Endocrinology, 141, 3183–3193.
Wankell M, Kaesler S, Zhang Y-Q, Florence C, Werner S and Duan R . (2001a). J. Endocrinol., 171, 385–395.
Wankell M, Munz B, Hübner G, Hans W, Wolf E, Goppelt A and Werner S . (2001b). EMBO J., 20, 5361–5372.
Welt C, Sidis Y, Keutmann H and Schneyer A . (2002). Exp. Biol. Med., 227, 724–752.
Willert J, Epping M, Pollack JR, Brown PO and Nusse R . (2002). BMC Dev. Biol., 2, 8.
Acknowledgements
We thank Dr Lambert and Martine De Mil for providing melanocyte cultures, Veronique Stove for help with retroviral transduction, Dr Shimasaki for the follistatin construct, Dr Nolan for the Phoenix amphotropic cell line, Dr Berx for CAGA and pUT reporter constructs and Isabel Vandenberghe for N-terminal sequencing. This work was supported by the Sportvereniging tegen Kanker and by the Belgian Federation for the Study of Cancer (BVSK). Christophe Stove is a research assistant with the Fund for Scientific Research-Flanders, which also provided the mass spectrometric instrumentation (Grant G.0312.02).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stove, C., Vanrobaeys, F., Devreese, B. et al. Melanoma cells secrete follistatin, an antagonist of activin-mediated growth inhibition. Oncogene 23, 5330–5339 (2004). https://doi.org/10.1038/sj.onc.1207699
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1207699
Keywords
This article is cited by
-
Upregulation of follistatin and low apoptotic activity in intraductal oncocytic papillary neoplasm of the pancreatobiliary system
Scientific Reports (2020)
-
TAK1 suppresses RIPK1-dependent cell death and is associated with disease progression in melanoma
Cell Death & Differentiation (2019)
-
Follistatin impacts Tumor Angiogenesis and Outcome in Thymic Epithelial Tumors
Scientific Reports (2019)
-
Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model
Journal of Investigative Dermatology (2015)
-
Follistatin as potential therapeutic target in prostate cancer
Targeted Oncology (2013)