Role of receptor complexes in resistance or sensitivity to growth inhibition by TGFβ in intestinal epithelial cell clones

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Abstract
Untransformed rat intestinal epithelial cells (IEC-18) were chemically mutagenized, selected in the presence of TGFβ1, and cloned by limiting dilution. Two clones (4–5, 4–6) were resistant to growth inhibition by both TGFβ1 and TGFβ2. Another clone (4–1) was more sensitive to both TGFβ isoforms (relative to parental IEC-18 cells). IC50 values for TGFβ1 and 2 in the 4–1 cells were at least 1/9 those of the parental cells; growth rates were reduced by 49% for TGFβ1 and by 26% for TGFβ2 in this clone. This increased sensitivity to TGFβ was explained by the 5- to 10-fold increase, relative to parental cells, in binding of TGFβ1 and TGFβ2 to both the type I and II receptors. In contrast, the resistance to growth inhibition by TGFβ in the 4–5 and 4–6 cells could not be explained by a decrease in either TGFβ binding affinities or in total number of receptors expressed, by the presence of serum binding components, or by occupation of receptor binding sites with autocrine TGF-β1. However, in comparison to TGFβ-sensitive cells (IEC-18, 4–1), the resistant cells displayed a higher ratio of type II relative to type I receptor binding by TGF-β1. Thus, a critical ratio of binding to receptor subtypes correlated with growth inhibition by TGF-β1. Resistance to TGF-β2 in the same clones did not appear to be receptor related. Thus different mechanisms for resistance to TGF-β1 and TGF-β2 were observed within a given clone.