Inhibitory effects of transforming growth factor beta 1 on mitogenic response, transforming growth factor alpha, 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 beta 1 (TGF-beta) 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-beta was ineffective in repressing nutrient-stimulated mitogenesis in quiescent, poorly differentiated cells. However, in quiescent, well-differentiated cells, TGF-beta repressed the mitogenic responses to both nutrients alone (by 90%) and to nutrients plus the exogenous stimulatory factors epidermal growth factor (E), insulin (I), and transferrin (T) (by 55-65%). Thymidine incorporation experiments indicated that TGF-beta reduced both the onset and peak mitogenic response to growth factors and/or nutrients in the well-differentiated cells. Additionally, TGF-beta repressed the growth factor (E + I + T)-stimulated upregulation of expression of both c-myc and of transforming growth factor alpha (TGF-alpha) mRNAs in quiescent, well-differentiated cells. TGF-beta also elicited a rapid (t1/2 approximately 1h) down-regulation of c-myc expression in the absence of prior growth factor (E + I + T) stimulation. In contrast, TGF-beta had no effect on c-myc or TGF-alpha mRNA expression in the poorly differentiated cells. The results suggest that TGF-beta exerts rapid inhibitory effects on proliferation-associated genes in quiescent and restimulated, well-differentiated cells. Expression of these genes (c-myc and TGF-alpha) may otherwise (in the absence of TGF-beta) play roles in the cellular signaling of mitogenic responses by growth stimulatory factors in well-differentiated colon carcinoma cells.