GnRH-Bik/Bax/Bak chimeric proteins target and kill adenocarcinoma cells; the general use of pro-apoptotic proteins of the Bcl-2 family as novel killing components of targeting chimeric proteins

In recent years chimeric proteins carrying bacterial toxins as their killin g moiety, have been developed to selectively recognize and kill cell popula tions expressing speciific receptors. The involvement of Gonadotropin relea sing hormone (GnRH) has been demonstrated in several adenocarcinomas and a GnRH-bacterial toxin chimeric protein (GnRH-PE66) was thus developed and fo und to specifically target and kill adenocarcinoma cells both in vitro and in vivo. Because of the immunogenicity and the non-specific toxicity of the bacterial toxins, we have developed new chimeric proteins, introducing apo ptosis inducing proteins of the Bcl-2 family as novel killing components. S equences encoding the human Bik, Bak or Bax proteins were fused to the GnRH coding sequence at the DNA level and were expressed in E. coli. GnRH-Bik, GnRH-Bak and GnRH-Bax new chimeric proteins efficiently and specifically in hibited the cell growth of adenocarcinoma cell lines and eventually led to cell death. All three Bcl2-proteins-based chimeric proteins seem to induce apoptosis within the target cells, without any additional cell death stimul us. Apoptosis-inducing-proteins of the Bcl-2 family targeted by the GnRH ar e novel potential therapeutic reagents for adenocarcinoma treatment in huma ns. This novel approach could be widely applied, using any molecule that bi nds a specific cell type, fused to an apoptosis-inducing protein.