UNDERSTANDING THE MOLECULAR BASIS OF CELL DEATH MEDIATED BY ONCOSIS-INDUCING CYTOTOXIC ANTIBODIES

Abstract

MONOCLONAL ANTIBODIES (MABS) A2, B3 AND B8, RAISED AGAINST HUMAN EMBRYONIC STEM CELLS, WERE FOUND TO SPECIFICALLY INDUCE ONCOSIS IN VARIOUS CANCER CELL LINES BUT NOT TO CORRESPONDING NORMAL CELL LINES. CHARACTERIZATION REVEALED THAT THESE MABS RECOGNIZED A GLYCAN MOIETY STRUCTURALLY RELATED TO BLOOD GROUP H TYPE-1 EXPRESSED ON MULTIPLE GLYCOPROTEINS ON THE PLASMA MEMBRANE. MECHANISM OF CYTOTOXICITY WAS FOUND TO INVOLVE DETACHMENT OF THE PLASMA MEMBRANE FROM THE UNDERLYING CYTOSKELETON THROUGH INACTIVATION OF EZRIN, RADIXIN AND MEOSIN, AND PERTURBATION TO CYTOSKELETON ORGANIZATION THROUGH DEGRADATION OF ACTIN-ASSOCIATED PAXILLIN, TALIN AND ALPHA-ACTININ. THE RESULTANT MEMBRANE INJURY WAS LIKELY EXACERBATED BY THE LOSS OF MYOSIN II ACTIVITY NECESSARY FOR MEMBRANE REPAIR. CYTOTOXICITY ALSO REQUIRED CROSSLINKING OF SURFACE GLYCOPROTEINS BY THE MABS AS MONOVALENT FAB FRAGMENTS DID NOT CAUSE CELL DEATH. THESE MABS ARE POTENTIAL BIOTHERAPEUTICS AS THEY BIND A TUMOUR-SPECIFIC EPITOPE AND EXHIB