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Alterations in TNF-alpha signal transduction in resistant human papillary thyroid carcinoma cells
X P Pang1, N S Ross, J M Hershman
1Thyroid Cancer Research Laboratory, West Los Angeles VA Medical Center, University of California 90073, USA.
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.
Insights
Tumor necrosis factor-alpha (TNF-alpha) resistance in papillary thyroid cancer (PTC) involves decreased p55 receptor signaling and increased p75 receptor signaling. Interferon-gamma (IFN-gamma) retains antiproliferative effects, impacting TNF receptor metabolism and MnSOD expression.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) inhibit human papillary thyroid carcinoma (PTC) cell growth.
- Development of TNF-alpha resistance in PTC cell lines (R30, R45, R60) was observed, while sensitivity to IFN-gamma remained.
- TNF-alpha receptor p55 mediates antiproliferative effects, while p75 does not in NP cells.
Purpose of the Study:
- Investigate the mechanisms underlying TNF-alpha resistance in PTC.
- Characterize the roles of TNF-alpha receptors (p55 and p75) in TNF-alpha-induced antiproliferation and resistance.
- Examine the impact of TNF-alpha and IFN-gamma on TNF receptor shedding and manganous superoxide dismutase (MnSOD) expression in resistant PTC cells.
Main Methods:
- Utilized TNF-alpha receptor-specific agonist monoclonal antibodies to assess receptor function.
- Analyzed TNF receptor shedding patterns in response to TNF-alpha and IFN-gamma.
- Measured basal and induced manganous superoxide dismutase (MnSOD) expression and mRNA levels.
Main Results:
- Resistant PTC cell lines exhibited graded loss of p55 receptor-mediated antiproliferation and activation of p75 receptor-mediated growth stimulation.
- TNF receptor shedding patterns were altered in resistant cells: decreased p75 shedding and increased p55 shedding.
- Resistant PTC cells showed increased basal MnSOD expression and blunted induction of MnSOD mRNA upon short-term TNF-alpha treatment.
Conclusions:
- Development of PTC cell resistance to TNF-alpha is associated with decreased p55 TNF-alpha receptor signaling and increased p75 TNF-alpha receptor signaling.
- Altered TNF receptor metabolism and changes in MnSOD expression are implicated in TNF-alpha resistance.
- IFN-gamma retains its antiproliferative efficacy against resistant PTC cells, suggesting differential therapeutic potential.