Positive and negative selection for tumor necrosis factor responsiveness reveals an inhibitory role for EGF receptor in TNF-induced antiproliferation.
Tumor necrosis factor (TNF) induces dose-dependent, but incomplete cytotoxicity in ME-180 cervical carcinoma cells resulting in a significant reduction in cell viability. In this cell line there exists a characteristic residual tumor cell population that appears to be resistant to TNF. In order to investigate tumor cell heterogeneity and characteristics that correlate with their escape from TNF-induced cytotoxicity, TNF-resistant ME-180 cell variants (ME-180R) were isolated from a population of ME-180 cervical carcinoma cells (ME-180 parental). Incubation of ME-180 parental cells with TNF resulted in measurable changes in tumor cell DNA structural integrity and dose-dependent cytotoxicity, whereas ME-180R cell growth and DNA integrity were not effected by incubation with TNF. Binding of 125I-labeled TNF to a TNF-specific cell-surface receptor was measurable and equivalent on both ME-180R and ME-180 parental cells and both cell lines predominantly expressed the p55 form of the TNF receptor based upon flow cytometric analysis. Although both cell lines shared similar doubling times, intrinsic EGF receptor tyrosine kinase activity in ME-180R cells was found to be > 3-fold higher than that isolated from ME-180 parental cells. These results suggest that TNF-responsiveness may be mediated at a point subsequent to TNF binding and may be regulated, in part, by the expression of tyrosine kinase activity. To further explore this hypothesis, A431 vulvular carcinoma cells that express resistance to TNF were cloned and variants were isolated that escaped EGF-induced growth inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Nishikawa
K
K
Department of Medical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston 77030.
Rotbein
J
J
Vijjeswarapu
D
D
Owen-Schaub
L
L
Rosenblum
M G
MG
Donato
N J
NJ
D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology*; D004273:DNA, Neoplasm / Q000378:metabolism; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D006801:Humans; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology; D014846:Vulvar Neoplasms / Q000378:metabolism / Q000473:pathology
D004273:DNA, Neoplasm; D014409:Tumor Necrosis Factor-alpha; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases