title: Interleukin-6 and 12-O-tetradecanoyl phorbol-13-acetate act synergistically in inducing cell-cell separation and migration of human breast carcinoma cells.
abstract: Interleukin-6 (IL-6) causes an epithelial to fibroblastoid conversion and an increase in the motility of human ductal breast carcinoma cell lines ZR-75-1 and T-47D. Although IL-6 decreases DNA synthetic activity in these cell lines, the IL-6-induced alterations in cell shape and motility occur independently of inhibition of DNA synthesis per se. Whereas tumor necrosis factor alpha (TNF-alpha) inhibits DNA synthesis in T-47D cells, it does not cause an epithelial-fibroblastoid conversion or other major morphological changes and does not increase cell motility; TNF-alpha rapidly lyses a majority of ZR-75-1 cells. Furthermore, the DNA synthesis inhibitors 5-fluoro-2'-deoxyuridine (FUDR) and methotrexate (MTX) also do not cause effects mimicking the action of IL-6 on cell structure and motility. Transforming growth factors alpha and beta 1, acidic and basic fibroblast growth factors, epidermal growth factor, and insulin-like growth factor-1 (TGF-alpha, TGF-beta 1, aFGF, bFGF, EGF, and IGF-1) have little or no effect on breast cancer cell morphology, which serves to exclude the possibility that the IL-6-induced changes are a consequence of induction of these growth factors by IL-6. 12-O-tetradecanoyl phorbol-13-acetate (TPA) but not 8-bromoadenosine 3',5'-cyclic monophosphate (Br-cAMP) induces changes in the morphology and associative behavior of ZR-75-1 cells that are similar but not identical to those caused by IL-6. The TPA-induced alterations are not blocked by anti-IL-6 neutralizing antibodies; staurosporine inhibits the TPA-induced cell alterations but not those induced by IL-6. IL-6 and TPA used together have a phenotypic effect that greatly exceeds that of either agent alone and results in extensive cell scattering in less than 1 day. These findings are consistent with the hypothesis that IL-6 and TPA induce similar morphological changes and cell scattering via independent pathways.
authors.affiliation: Rockefeller University, New York, NY 10021.
authors.forename: I
authors.initials: I
authors.lastname: Tamm
authors.forename: I
authors.initials: I
authors.lastname: Cardinale
authors.forename: P B
authors.initials: PB
authors.lastname: Sehgal
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000911:Antibodies, Monoclonal; D001943:Breast Neoplasms / Q000473:pathology / Q000503:physiopathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000473:pathology / Q000503:physiopathology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005467:Floxuridine / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology*; D008727:Methotrexate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D015290:Second Messenger Systems / Q000187:drug effects; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D000470:Alkaloids; D000911:Antibodies, Monoclonal; D016207:Cytokines; D006133:Growth Substances; D015850:Interleukin-6; D011994:Recombinant Proteins; D005467:Floxuridine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D008727:Methotrexate