Inhibitory Effects of Transforming Growth Factor β x on Mitogenic Response, Transforming Growth Factor a, and c-myc in Quiescent, Well-Differentiated Colon Carcinoma Cells

Previously, we reported that exponentially proliferating cultures of well-differentiated human colon carcinoma cells responded to transforming growth factor β x (TGF-/9) with growth inhibition, alterations in morphology, and increased secretion of the differentiation marker, carcinoembryonic antigen. Poorly differentiated cultures were unresponsive. Here we show that TGF-0 was ineffective in repressing nutrient-stimulated mitogenesis in quiescent, poorly differentiated cells. However, in quiescent, well-differentiated cells, TGF-0 repressed the mitogenic responses to both nutrients alone (by 90%) and to nutrients plus the exogenous stimulatory factors epidermal growth factor (E), insulin (IX and transferrin (T) (by 55–65%). Thymidine incorporation experiments indicated that TGF-0 reduced both the onset and peak mitogenic response to growth factors and/or nutrients in the well-differentiated cells. Additionally, TGF-/9 repressed the growth factor (E + I + T)-stimulated up-regulation of expression of both c-myc and of transforming growth factor a (TGF-o) mRNAs in quiescent, well-differentiated cells. TGF-0 also elicited a rapid (t½ ≈1h) down-regulation of c-myc expression in the absence of prior growth factor (E + I + T) stimulation. In contrast, TGF- β had no effect on c-myc or TGF-a mRNA expression in the poorly differentiated cells. The results suggest that TGF- β exerts rapid inhibitory effects on proliferation-associated genes in quiescent and restimulated, well-differentiated cells. Expression of these genes (c-myc and TGF-a) may otherwise (in the absence of TGF- β) play roles in the cellular signaling of mitogenic responses by growth stimulatory factors in well-differentiated colon carcinoma cells.