Human beta2-adrenergic receptor/GS alpha fusion protein, expressed in 2 ras-dependent murine carcinoma cell lines, prevents tumor growth in syngeneic mice.
We report a strategy of tumor growth inhibition based on the expression of a foreign protein with both potential anti-proliferative and immunogenic properties. To validate our approach, we used 2 ras-mutated murine carcinoma cell lines (carB and C57/PDV) transfected with the gene encoding a fusion protein containing the human beta2-adrenergic receptor and the alpha subunit of the Gs protein (beta2Gs). We previously showed that the sustained activation of the beta2Gs fusion protein expressed in carB cells (carB beta2Gs cells) induced a cAMP-dependent inhibition of cell growth in vitro. Here, we observed inhibition of tumor growth after s.c. inoculation of 2 carB beta2Gs clones (10C2 and 20F4) in syngeneic ICFW mice. We thus selected 3 C57/PDV beta2Gs clones (2D3, 5F3 and 1G1) in which activation of the fusion protein was not efficiently coupled to the cAMP-PKA signaling pathway. Contrasting with carB beta2Gs clones, activation of the fusion protein in these C57/PDV beta2Gs clones did not have any anti-proliferative effect in vitro. Therefore, they were good candidates to assess the immunogenic property of the fusion protein. Accordingly, none of the C57/PDV beta2Gs clones formed tumors in immunocompetent syngeneic C57BL/6 mice, while they were still tumorigenic in nude mice. Most interestingly, all of the beta2Gs clones that did not form tumors, from both cell lines, provided protection against respective wild-type tumor development. Our results show that expression of the beta2Gs fusion protein in cancer cells elicits inhibition of cell proliferation and/or immune rejection of both beta2Gs-modified and wild-type tumor cells.
Bertin
B
B
Institut Cochin de Génétique Moléculaire, CNRS UPR 415 and University of Paris, France.
Strosberg
A D
AD
Marullo
S
S
D000818:Animals; D002455:Cell Division / Q000235:genetics; D002999:Clone Cells; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D011905:Genes, ras; D015316:Genetic Therapy; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014407:Tumor Cells, Cultured
D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs