Bystander effects are induced by CENU treatment and associated with altered protein secretory activity of treated tumor cells: a relay for chemotherapy?
In a previous study, it was reported that secondary untreated melanoma tumors implanted several weeks after and at distance from primary chloroethylnitrosourea (CENU)-treated tumors underwent differentiation and growth inhibition. To see whether the primary treated tumor released soluble factors that mediated the secondary tumor response, serum transfer experiments were performed in vivo. Administration of serum from CENU-treated tumor-bearing donors arrested tumor proliferation, decreased vessel formation and induced tumor metabolite alterations encompassing glutathione decrease and polyunsaturated fatty acid and phosphoethanolamine increase. These changes mimicked secondary tumor phenotype. To reproduce the model in vitro, cell culture supernatant transfer experiments were performed. CENU-treated cell cultures showed polyploidy and reactive oxygen species (ROS) production. Cell cultures challenged by a conditioned medium of CENU-treated cells underwent growth inhibition, cytoskeleton disorders, cytokinesis retardation, metabolite alterations, glutathione decrease and phosphoethanolamine increase, without ROS elicitation. Proteomics of CENU-treated cell conditioned media revealed altered protein secretion activity by CENU-treated cells. Among de novo secreted proteins, the most expressed were phosphatidylethanolamine-binding protein (PEBP), cardiovascular heat shock protein (cHsp), Rho-associated coiled-coil forming kinase 2 (ROCK) and actin fragments. These proteins testified of cytoskeleton disorders, growth inhibition and metabolite alterations. This article demonstrates the release by CENU-treated tumors of growth inhibitory differentiation-inducing soluble factors. These factors mediate remote bystander effects and attest persistent biological activity of residual tumors after chemotherapy.
Demidem
Aicha
A
UMR INSERM, Clermont-Ferrand, France.
Morvan
Daniel
D
Madelmont
Jean Claude
JC
D000199:Actins / Q000032:analysis; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D024201:Bystander Effect / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D015180:Electrophoresis, Gel, Two-Dimensional; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000032:analysis* / Q000187:drug effects / Q000378:metabolism; D049488:Phosphatidylethanolamine Binding Protein / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases
D000199:Actins; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D049488:Phosphatidylethanolamine Binding Protein; C017139:1-(2-chloroethyl)-1-nitrosourea; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D005038:Ethylnitrosourea