Isolation and Characterization of a Rat Liver Epithelial Cell Line Resistant to the Antiproliferative Effects of Transforming Growth Factor β (Type 1)

Munal S. Chapekar, Anthony C. Huggett, Caroline C. Cheng, Lori L. Hampton, K. H. Lin, Snorri S. Thorgeirsson*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

10 Scopus citations

Abstract

Rat liver epithelial cells resistant to the growth-inhibitory effects of transforming growth factor β1 (TGF-β#x03B2;1) were isolated after 3 h exposure to 1.5 μg/ml of N-methyl-.N′-nitro-N-nitrosoguanidine followed by continuous treatment with 1 ng/ml TGF-β#x03B2;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-β1 and exhibited resistance to growth inhibition by a highly purified liver-derived growth inhibitor, recombinant human tumor necrosis factor, and transforming growth factor β2. 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-β, treatment. Binding of 125I-labeled TGF-β, 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-β1, and c-myc genes. The data presented here suggest an association between resistance to the growth-inhibitory effects of TGF-β1- and MDR-1-mediated multidrug resistance.

Original languageEnglish
Pages (from-to)3600-3604
Number of pages5
JournalCancer Research
Volume50
Issue number12
StatePublished - 15 06 1990
Externally publishedYes

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