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pp60v-src kinase overexpression leads to cellular resistance to the antiproliferative effects of tumor necrosis
B B Aggarwal1, K Totpal, F Ali-Osman
1Department of Clinical Immunology and Biological Therapy, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Abstract:
While some tumor cells are sensitive to the antiproliferative effects of tumor necrosis factor (TNF), others are resistant. The molecular basis for cellular resistance to TNF is not completely understood. Previously we have shown that transfection of cells with an oncogene HER2/neu/erb B2, a receptor tyrosine kinase, leads to resistance to the anticellular effects of TNF [(1988) Proc. Natl. Acad. Sci. USA 85, 5102-5106]. In the present study, we demonstrate that the overexpression of another oncogenic tyrosine kinase, pp60v-src also induces resistance to TNF. In contrast to HER2, however, pp60v-src transfection of cells did not lead to down-modulation of TNF receptors but rather to decreased intracellular glutathione levels. The pp60v-src-induced cellular resistance to TNF could be abrogated by interferon-gamma. Thus, these results indicate that the resistance of certain tumors to TNF may also be due in part to the overexpression of pp60v-src oncogene.
Insights
Oncogenic tyrosine kinase pp60v-src overexpression confers resistance to tumor necrosis factor (TNF) in tumor cells. Interferon-gamma can reverse this resistance, suggesting pp60v-src
Area of Science:
- Molecular Biology
- Cancer Research
- Immunology
Background:
- Cellular resistance to tumor necrosis factor (TNF) is a significant challenge in cancer therapy.
- The molecular mechanisms underlying TNF resistance are not fully elucidated.
- Previous studies linked HER2/neu/erb B2 oncogene overexpression to TNF resistance.
Purpose of the Study:
- To investigate the role of the oncogenic tyrosine kinase pp60v-src in cellular resistance to TNF.
- To compare the resistance mechanisms induced by pp60v-src with those induced by HER2.
- To explore potential strategies to overcome pp60v-src-mediated TNF resistance.
Main Methods:
- Transfection of cells with the pp60v-src oncogene.
- Assessment of TNF receptor expression levels.
- Measurement of intracellular glutathione levels.
- Evaluation of the effect of interferon-gamma on TNF resistance.
Main Results:
- Overexpression of pp60v-src induced cellular resistance to TNF.
- Unlike HER2, pp60v-src did not down-modulate TNF receptors.
- pp60v-src transfection led to decreased intracellular glutathione levels.
- Interferon-gamma abrogated the pp60v-src-induced TNF resistance.
Conclusions:
- Overexpression of the pp60v-src oncogene is a novel mechanism contributing to tumor cell resistance to TNF.
- pp60v-src-induced TNF resistance involves decreased intracellular glutathione, distinct from HER2-mediated resistance.
- Interferon-gamma represents a potential therapeutic approach to sensitize tumors to TNF therapy when pp60v-src is overexpressed.