This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Roque-Navarro, L. Articles by Pérez, R. PubMed PubMed Citation Articles by Roque-Navarro, L. Articles by Pérez, R.

Research Articles: Therapeutics, Targets, and Development

Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity

¹ Antibody Engineering Department, Centre of Molecular Immunology; ² Electronic Microscopy Department, National Centre of Scientific Investigations; ³ Criminality Central Laboratory, Havana, Cuba and ⁴ Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, Nice France

Requests for reprints: Rolando Pérez, Antibody Engineering Department, Centre of Molecular Immunology, 216 Street and 15th Avenue, Atabey, Playa, Havana, 11600 Cuba. Phone: 53-7-2716810; Fax: 53-7-2720644. E-mail: rolando{at}cim.sld.cu

Abstract

Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid–containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4⁺ T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab')₂ but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy. [Mol Cancer Ther 2008;7(7):2033–41]

Grant support: Boehringer Ingelheim Fonds and International Union Against Cancer fellowships and the Cuban Government (L. Roque-Navarro) and Susan G. Komen Breast Cancer Foundation postdoctoral fellowship (K. Chakrabandhu).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 3/ 4/08; accepted 4/ 2/08.