Skip to main content

Advertisement

SpringerLink
Log in

CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants

  • Original Paper
  • Published:
Oncogene Submit manuscript

Abstract

The significance of CD95/Fas ligand expression by melanoma cells has remained a controversial matter in recent years. On the other hand, CD95 activation may represent a powerful tool for eliminating tumor cells. Here, we demonstrate expression of CD95 in 15/17 human melanoma cell lines analysed, but complete lack of CD95 ligand (CD95L). Overexpression of CD95 in a tetracycline-inducible expression system enhanced melanoma cell sensitivity to CD95 ligation but was unable to trigger apoptosis by itself. In clear contrast, all melanoma cells tested responded with increased apoptosis to conditional expression of CD95L (2–10-fold), both after transient and after stable transfection. Activation of caspase-8, Bid cleavage, cytochrome c release and caspase-3 activation followed after CD95L induction indicating a functional CD95-signaling cascade. CD95L was also able to enhance the proapoptotic effect of chemotherapeutics applied in parallel. Nude mouse experiments revealed that tumorigenicity was lost when melanoma xenografts were triggered to express CD95L. In addition, further progression of pre-existing melanomas was inhibited and even regression was seen after induction of CD95L expression. Due to these data, transfection of CD95L proofs as a highly efficient tool against melanoma cells in vitro and in vivo, and targeted expression of CD95L may thus represent a suitable strategy for melanoma therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10

Similar content being viewed by others

References

  • Ambar BB, Frei K, Malipiero U, Morelli AE, Castro MG, Lowenstein PR and Fontana A . (1999). Hum. Gene Ther., 10, 1641–1648.

  • Andreola G, Rivoltini L, Castelli C, Huber V, Perego P, Deho P, Squarcina P, Accornero P, Lozupone F, Lugini L, Stringaro A, Molinari A, Arancia G, Gentile M, Parmiani G and Fais S . (2002). J. Exp. Med., 195, 1303–1316.

  • Aragane Y, Maeda A, Cui CY, Tezuka T, Kaneda Y and Schwarz T . (2000). J. Invest. Dermatol., 115, 1008–1014.

  • Arai H, Gordon D, Nabel EG and Nabel GJ . (1997). Proc. Natl. Acad. Sci. USA, 94, 13862–13867.

  • Bean MA, Bloom BR, Herberman RB, Old LJ, Oettgen HF, Klein G and Terry WD . (1975). Cancer Res., 35, 2902–2913.

  • Behrens CK, Igney FH, Arnold B, Moller P and Krammer PH . (2001). J. Immunol., 166, 3240–3247.

  • Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, Faltin H, Bamberg M, Budach W and Schulze-Osthoff K . (2000). Oncogene, 19, 1181–1190.

  • Belka C, Schmid B, Marini P, Durand E, Rudner J, Faltin H, Bamberg M, Schulze-Osthoff K and Budach W . (2001). Oncogene, 20, 2190–2196.

  • Bruggen J, Macher E and Sorg C . (1981). Cancer Immunol. Immunother., 10, 121–127.

  • Bullani RR, Wehrli P, Viard-Leveugle I, Rimoldi D, Cerottini JC, Saurat JH, Tschopp J and French LE . (2002). Melanoma Res., 12, 263–270.

  • Carey TE, Takahashi T, Resnick LA, Oettgen HF and Old LJ . (1976). Proc. Natl. Acad. Sci. USA, 73, 3278–3282.

  • Chappell DB, Zaks TZ, Rosenberg SA and Restifo NP . (1999). Cancer Res., 59, 59–62.

  • Cohen GM . (1997). Biochem. J., 326, 1–16.

  • Coney LR, Daniel PT, Sanborn D, Dhein J, Debatin KM, Krammer PH and Zurawski Jr VR . (1994). Int. J. Cancer, 58, 562–567.

  • Daniel PT, Wieder T, Sturm I and Schulze-Osthoff K . (2001). Leukemia, 15, 1022–1032.

  • Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P and Krammer PH . (1992). J. Immunol., 149, 3166–3173.

  • Eberle J, Fecker LF, Bittner J-U, Orfanos CE and Geilen CC . (2002). Br. J. Cancer, 86, 1957–1962.

  • Eberle J, Garbe C and Orfanos CE . (1995). Arch. Dermatol. Res., 287, 421–427.

  • Eisinger M and Marco O . (1982). Proc. Natl. Acad. Sci. USA, 79, 2018–2022.

  • Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K and Wesselborg S . (2000). Oncogene, 19, 4563–4573.

  • Fischer U, Janicke RU and Schulze-Osthoff K . (2003). Cell Death Differ., 10, 76–100.

  • Gossen M and Bujard H . (1992). Proc. Natl. Acad. Sci. USA, 89, 5547–5551.

  • Gross A . (2001). IUBMB Life, 52, 231–236.

  • Hahne M, Rimoldi D, Schroter M, Romero P, Schreier M, French LE, Schneider P, Bornand T, Fontana A, Lienard D, Cerottini J and Tschopp J . (1996). Science, 274, 1363–1366.

  • Hedlund TE, Meech SJ, Srikanth S, Kraft AS, Miller GJ, Schaack JB and Duke RC . (1999). Cell Death Differ., 6, 175–182.

  • Helmbach H, Rossmann E, Kern MA and Schadendorf D . (2001). Int. J. Cancer, 93, 617–622.

  • Ivanov VN, Bhoumik A and Ronai Z . (2003). Oncogene, 22, 3152–3161.

  • Kaufmann SH and Earnshaw WC . (2000). Exp. Cell Res., 256, 42–49.

  • Krammer PH . (2000). Nature, 407, 789–795.

  • Lockshin A, Giovanella BC, De Ipolyi PD, Williams Jr LJ, Mendoza JT, Yim SO and Stehlin JSJ . (1985). Cancer Res., 45, 345–350.

  • Lynch DH, Watson ML, Alderson MR, Baum PR, Miller RE, Tough T, Gibson M, Davis-Smith T, Smith CA and Hunter K . (1994). Immunity, 1, 131–136.

  • Mariani SM, Matiba B, Baumler C and Krammer PH . (1995). Eur. J. Immunol., 25, 2303–2307.

  • Muschen M, Warskulat U and Beckmann MW . (2000). J. Mol. Med., 78, 312–325.

  • Nagata S and Golstein P . (1995). Science, 267, 1449–1456.

  • O'Connell J, O'Sullivan GC, Collins JK and Shanahan F . (1996). J. Exp. Med., 184, 1075–1082.

  • Oehm A, Behrmann I, Falk W, Pawlita M, Maier G, Klas C, Li-Weber M, Richards S, Dhein J and Trauth BC . (1992). J. Biol. Chem., 267, 10709–10715.

  • Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T and Nagata S . (1993). Nature, 364, 806–809.

  • Okamoto S, Takamizawa S, Bishop W, Wen J, Kimura K and Sandler A . (1999). J. Surg. Res., 84, 77–81.

  • Park BJ, Brown CK, Hu Y, Alexander HR, Horti J, Raje S, Figg WD and Bartlett DL . (1999). Hum. Gene Ther., 10, 889–898.

  • Pruschy M, Rocha S, Zaugg K, Tenzer A, Hess C, Fisher DE, Glanzmann C and Bodis S . (2001). Int. J. Radiat. Oncol. Biol. Phys., 49, 561–567.

  • Radetzki S, Köhne CH, von Haefen C, Gillissen B, Sturm I, Dörken B and Daniel PT . (2002). Oncogene, 21, 227–238.

  • Raisova M, Bektas M, Wieder T, Daniel PT, Eberle J, Orfanos CE and Geilen CC . (2000). FEBS Lett., 473, 27–32.

  • Raisova M, Hossini AM, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE and Geilen CC . (2001). J. Invest. Dermatol., 117, 333–340.

  • Redondo P, Solano T, VAzquez B, Bauza A and Idoate M . (2002). Br. J. Dermatol., 147, 80–86.

  • Seino K, Kayagaki N, Okumura K and Yagita H . (1997). Nat. Med., 3, 165–170.

  • Shinoura N, Yoshida Y, Asai A, Kirino T and Hamada H . (2000). Cancer Gene Ther., 7, 732–738.

  • Sieg S, Smith D and Kaplan D . (1999). Cell. Immunol., 195, 89–95.

  • Strater J, Walczak H, Hasel C, Melzner I, Leithauser F and Moller P . (2001). Cell Death Differ., 8, 273–278.

  • Suda T, Hashimoto H, Tanaka M, Ochi T and Nagata S . (1997). J. Exp. Med., 186, 2045–2050.

  • Timmer T, de Vries EG and de Jong S . (2002). J. Pathol., 196, 125–134.

  • Trauth BC, Klas C, Peters AM, Matzku S, Moller P, Falk W, Debatin KM and Krammer PH . (1989). Science, 245, 301–305.

  • von Haefen C, Wieder T, Gillissen B, Stärck L, Graupner V, Dörken B and Daniel PT . (2002). Oncogene, 21, 4009–4019.

  • Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dörken B and Daniel PT . (2001). Blood, 97, 1378–1387.

  • Wieder T, Orfanos CE and Geilen CC . (1998). J. Biol. Chem., 273, 11025–11031.

Download references

Acknowledgements

The study was supported by the Deutsche Krebshilfe/Mildred-Scheel-Stiftung (grant 10-1434-Eb1/2). AMH was a recipient of a scholarship of the Free University of Berlin. We thank Klaus Schulze-Osthoff (Department for Molecular Medicine, Heinrich Heine University Düsseldorf, Germany) for supplying us with caspase-8 antibodies.

Author information

Authors and Affiliations

  1. Department of Dermatology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, 14195, Germany

    Jürgen Eberle, Lothar F Fecker, Amir M Hossini, Constantin E Orfanos & Christoph C Geilen

  2. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité Campus Berlin-Buch, Humboldt University Berlin, Berlin, 13125, Germany

    Thomas Wieder & Peter T Daniel

Authors
  1. Jürgen Eberle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lothar F Fecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amir M Hossini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Thomas Wieder
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter T Daniel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Constantin E Orfanos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christoph C Geilen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jürgen Eberle.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Eberle, J., Fecker, L., Hossini, A. et al. CD95/Fas signaling in human melanoma cells: conditional expression of CD95L/FasL overcomes the intrinsic apoptosis resistance of malignant melanoma and inhibits growth and progression of human melanoma xenotransplants. Oncogene 22, 9131–9141 (2003). https://doi.org/10.1038/sj.onc.1207228

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207228

  • Springer Nature Limited

Keywords

This article is cited by

Search

Navigation