Overexpression of protectin (CD59) down-modulates the susceptibility of human melanoma cells to homologous complement.

Abstract

The clinical efficacy of therapeutic complement (C)-activating monoclonal antibodies (mAb) to melanoma-associated antigens can be impaired by the levels of expression of C-inhibitory molecules on neoplastic cells. Protectin (CD59) is a glycosylphosphatidylinositol (GPI)-anchored cell membrane glycoprotein, acting as terminal regulator of C cascade, which is heterogeneously expressed in melanomas and represents the main restriction factor of C-mediated lysis of melanoma cells. Thus, we investigated whether the overexpression of CD59 could influence the constitutive susceptibility of distinct melanoma cells to homologous C. Infection of CD59-positive Mel 100 and 70-W melanoma cells by a retroviral vector carrying the CD59 cDNA, significantly (P < 0.05) upregulated their constitutive expression of CD59, whereas it did not affect that of additional C-regulatory molecules. Transduced CD59 was entirely GPI-anchored and showed a molecular weight identical to native CD59. Additionally, higher amounts of soluble CD59 were detected in the conditioned media of CD59-transduced melanoma cells compared with parental cells. CD59-transduced melanoma cells, sensitized by the anti-GD3 disialoganglioside mAb R24, were significantly (P < 0.05) less susceptible to homologous C-lysis than were parental cells; this effect was fully reverted by the masking of CD59 with F(ab')(2) fragments of the anti-CD59 mAb YTH53.1. These results provide conclusive evidence demonstrating that absolute levels of CD59 expression regulate the susceptibility to homologous C of specific melanoma cells, and suggest an additional explanation for the poor clinical results obtained with C-activating mAb in the clinical setting.

• Authors: S Coral, E Fonsatti, L Sigalotti, C De Nardo, A Visintin, G Nardi, F Colizzi, M P Colombo, G Romano, M Altomonte, M Maio
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 185 Issue 3 Pg. 317-23 (Dec 2000) ISSN: 0021-9541 [Print] United States
• PMID: 11056001 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2000 Wiley-Liss, Inc.

Chemical References

• CD59 Antigens

Topics

• CD59 Antigens (biosynthesis, genetics)
• Complement Activation (genetics)
• Down-Regulation
• Gene Expression Regulation, Neoplastic (immunology)
• Genetic Vectors
• Humans
• Melanoma (genetics, immunology)
• Retroviridae
• Transfection
• Tumor Cells, Cultured