Alterations in TNF-α Signal Transduction in Resistant Human Papillary Thyroid Carcinoma Cells

Tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) inhibit the growth of the human papillary thyroid carcinoma (PTC) cell line, NP. Exposure of NP cells to TNF-γ resulted in the development of several PTC cell lines (R30, R45, and R60) with graded loss to the TNF-α-induced antiproliferation, termed resistance. In contrast, the NP cells and the resistant cells were equally sensitive to the antiproliferative action of interferon-γ. Utilizing TNF-α receptor-specific agonist monoclonal antibodies, we demonstrated that the TNF-α receptor p⁵⁵ mediated the antiproliferative action of TNF-α, 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-α receptor metabolism. The p⁵⁵ receptor mediated the TNF-α-induced up-regulation of the shedding of the p⁷⁵ TNF-α receptor. The p⁷⁵ receptor mediated the TNF-α-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-α. In contrast, IFN-γ increased shedding of both p⁵⁵ and p⁷⁵ TNF-α 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-α treatment (less than 2 h of treatment). The results indicate that a decrease in signal transduction via the p⁵⁵ TNF-α receptor and concomitant increase in signal transduction via the p⁷⁵ TNF-α receptor are involved in the development of PTC cell resistance.