耐药性人甲状腺乳头状癌细胞中肿瘤坏死因子-α信号转导的改变。

Alterations in TNF-alpha signal transduction in resistant human papillary thyroid carcinoma cells.

作者信息

Pang X P, Ross N S, Hershman J M

机构信息

Thyroid Cancer Research Laboratory, West Los Angeles VA Medical Center, University of California 90073, USA.

出版信息

Thyroid. 1996 Aug;6(4):313-7. doi: 10.1089/thy.1996.6.313.

DOI:10.1089/thy.1996.6.313

PMID:8875753

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.

摘要

肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）可抑制人甲状腺乳头状癌（PTC）细胞系NP的生长。将NP细胞暴露于TNF-α会导致几种PTC细胞系（R30、R45和R60）的产生，这些细胞系对TNF-α诱导的抗增殖作用呈梯度性丧失，即产生抗性。相比之下，NP细胞和抗性细胞对干扰素-γ的抗增殖作用同样敏感。利用TNF-α受体特异性激动剂单克隆抗体，我们证明TNF-α受体p55介导了TNF-α的抗增殖作用，而p75受体对NP细胞系中的细胞增殖没有影响。然而，抗性PTC细胞系显示出p55受体介导的抗增殖作用呈梯度性丧失，同时p75受体介导的生长刺激作用被激活。TNF受体的脱落是TNF-α受体代谢的重要机制。p55受体介导了TNF-α诱导的p75 TNF-α受体脱落的上调。p75受体介导了TNF-α诱导的p55受体脱落的下调。然而，与NP细胞系相比，在存在和不存在TNF-α的情况下，抗性R60细胞系中p75受体的脱落减少，p55受体的脱落增加。相比之下，IFN-γ以相同效力增加了NP和R60细胞系中p55和p75 TNF-α受体的脱落。此外，抗性PTC细胞系的基础锰超氧化物歧化酶（MnSOD）表达增加，且短期TNF-α处理（处理时间少于2小时）后MnSOD mRNA的诱导减弱。结果表明，通过p55 TNF-α受体的信号转导减少以及通过p75 TNF-α受体的信号转导同时增加与PTC细胞抗性的产生有关。