TRANSFORMING GROWTH-FACTOR-BETA-1 RESISTANCE IN A THYROID-CANCER MODEL OF TUMOR-NECROSIS-FACTOR-ALPHA RESISTANCE

We have shown that both tumor necrosis factor-alpha (TNF-alpha) and tr ansforming growth factor-beta 1 (TGF-beta 1) inhibit the growth of the human papillary thyroid carcinoma (PTC) cell line, NPA. In previous w ork, we developed NPA cells that were resistant to the growth suppress ive effect of TNF-alpha, called R30, R45, and R60. In this model there were alterations in the p55 and p75 TNF-alpha receptor signaling in t he resistant cell lines. In the present work, we studied the action of TGF-beta 1 in this PTC cell model. TGF-beta 1 (111 pg/mL) inhibited t he proliferation of NPA, R30, R45, and the R60 cell lines by 82.8%, 72 .1%, 64.2%, and 24.2%, respectively. On Western analysis, TGF-beta 1 r educed c-fos content with similar potency in the NPA and R60 cells. In contrast, TNF-alpha reduced c-fos content in the sensitive NPA cells, but failed to do so in the resistant R60 cells. TGF-beta 1 reduced p5 3 content in the NPA but not in the R60 cells, while TNF-alpha did not affect the p53 content in these cells. Furthermore, the resistant cel ls had a lower baseline p53 content than the NPA cells, The resistant cells had a significantly increased growth rate. Enzyme-linked immunos orbent assay (ELISA) assays with specific antibody against human p53 s howed no apparent increase in the mutant form of p53 in the resistant cells. There were also no mutant forms of Ha-Ras, Arg(12)p21, Val(12)p 21, Asp(12)p21, and Asp(13)p21 detected in the resistant cells. The re sults showed that R30, R45, and R60 cells are partially resistant to T GF beta 1. The mechanisms of action of TNF-alpha and TGF-beta 1 differ in their regulation of c-fos and p53 content. The increase in cell pr oliferation rate is apparently associated with a decrease of p53 conte nt, but not with mutations of p53 or Ha-Ras.