title: Alterations in TNF-alpha signal transduction in resistant human papillary thyroid carcinoma cells.
abstract: Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) inhibit the growth of the human papillary thyroid carcinoma (PTC) cell line, NP. Exposure of NP cells to TNF-alpha resulted in the development of several PTC cell lines (R30, R45, and R60) with graded loss to the TNF-alpha-induced antiproliferation, termed resistance. In contrast, the NP cells and the resistant cells were equally sensitive to the antiproliferative action of interferon-gamma. Utilizing TNF-alpha receptor-specific agonist monoclonal antibodies, we demonstrated that the TNF-alpha receptor p55 mediated the antiproliferative action of TNF-alpha, while the p75 receptor did not affect cell proliferation in the NP cell line. The resistant PTC cell lines, however, showed a graded loss of p55 receptor-mediated antiproliferation and a concomitant activation of a p75 receptor-mediated growth stimulation. Shedding of TNF receptors is an important mechanism of TNF-alpha receptor metabolism. The p55 receptor mediated the TNF-alpha-induced up-regulation of the shedding of the p75 TNF-alpha receptor. The p75 receptor mediated the TNF-alpha-induced down-regulation of the shedding of the p55 receptor. However, the shedding of the p75 receptor was decreased and the shedding of the p55 receptor was increased in the resistant R60 cell line compared with the NP cell line, in the presence and absence of TNF-alpha. In contrast, IFN-gamma increased shedding of both p55 and p75 TNF-alpha receptors in NP and R60 cell lines with equal potency. Furthermore, the resistant PTC cell lines have increased basal manganous superoxide dismutase (MnSOD) expression and blunted induction of MnSOD mRNA upon short-term. TNF-alpha treatment (less than 2 h of treatment). The results indicate that a decrease in signal transduction via the p55 TNF-alpha receptor and concomitant increase in signal transduction via the p75 TNF-alpha receptor are involved in the development of PTC cell resistance.
authors.affiliation: Thyroid Cancer Research Laboratory, West Los Angeles VA Medical Center, University of California 90073, USA.
authors.forename: X P
authors.initials: XP
authors.lastname: Pang
authors.forename: N S
authors.initials: NS
authors.lastname: Ross
authors.forename: J M
authors.initials: JM
authors.lastname: Hershman
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D015152:Blotting, Northern; D002291:Carcinoma, Papillary / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000096:biosynthesis; D013964:Thyroid Neoplasms / Q000503:physiopathology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013482:Superoxide Dismutase