pp60v-src kinase overexpression leads to cellular resistance to the antiproliferative effects of tumor necrosis factor.
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.
Aggarwal
B B
BB
Department of Clinical Immunology and Biological Therapy, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Totpal
K
K
Ali-Osman
F
F
Budde
R J
RJ
Pocsik
E
E
D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D015536:Down-Regulation; D004351:Drug Resistance / Q000502:physiology*; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000096:biosynthesis* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis*; D011994:Recombinant Proteins; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*
D066246:ErbB Receptors; D005978:Glutathione; D007371:Interferon-gamma; D015688:Oncogene Protein pp60(v-src); D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha