Isolation and characterization of a rat liver epithelial cell line resistant to the antiproliferative effects of transforming growth factor beta (type 1).
Rat liver epithelial cells resistant to the growth-inhibitory effects of transforming growth factor beta 1 (TGF-beta 1) were isolated after 3 h exposure to 1.5 micrograms/ml of N-methyl-N'-nitro-N-nitrosoguanidine followed by continuous treatment with 1 ng/ml TGF-beta 1 for 6 weeks. In comparison to the parental or N-methyl-N'-nitro-N-nitrosoguanidine-exposed rat liver epithelial cells (concentration causing 50% inhibition of the rate of DNA synthesis, 0.25 ng/ml), these cells were 10-fold more resistant to the antiproliferative effects of TGF-beta 1 and exhibited resistance to growth inhibition by a highly purified liver-derived growth inhibitor, recombinant human tumor necrosis factor, and transforming growth factor beta 2. Single cell cloning of these resistant cells led to the isolation of a nontransformed clonal cell population (clone 11) which maintained stable resistance in the absence of TGF-beta 1 treatment. Binding of 125I-labeled TGF-beta 1 to rat liver epithelial cells and clone 11 cells was similar. Clone 11 cells exhibited a 5-10-fold resistance to the cytotoxins Adriamycin and vinblastine as assessed by a clonogenic assay. This drug resistance was accompanied by an increase in the steady state levels of the mRNAs for multidrug resistance gene (MDR-1), glutathione S-transferase-P, TGF-beta 1, and c-myc genes. The data presented here suggest an association between resistance to the growth-inhibitory effects of TGF-beta 1- and MDR-1-mediated multidrug resistance.
Chapekar
M S
MS
Division of Cancer Etiology, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Huggett
A C
AC
Cheng
C C
CC
Hampton
L L
LL
Lin
K H
KH
Thorgeirsson
S S
SS
D000818:Animals; D001119:Arginase; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004848:Epithelium; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008769:Methylnitronitrosoguanidine; D011506:Proteins / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015291:Transforming Growth Factors / Q000378:metabolism / Q000494:pharmacology*
D011506:Proteins; D012333:RNA, Messenger; D008769:Methylnitronitrosoguanidine; D015291:Transforming Growth Factors; D001119:Arginase