Ligand induced upregulation of the type II transforming growth factor (TGF-beta) receptor enhances TGF-beta responsiveness in COLO-357 cells

The effects of transforming growth factor (TGF)-beta 1 on type I and type I I TGF-beta receptor (T beta RI and T beta RII) expression were examined in five pancreatic cancer cell lines. In contrast to its actions in COLO-357, a TGF-beta-sensitive pancreatic cancer cell line, TGF-beta 1 did not signif icantly alter TGF-beta receptor expression in either the TGF-beta-sensitive : BX-PC-3 and PANC-1 cells or in the TGF-beta-resistant CAPAN-1 and T3M4 ce lls. Neutralizing anti-T beta RII antibodies blocked TGF-beta 1-dependent s ignaling in COLO-357 cells but exhibited an attenuated effect in COLO-357 c ells preincubated with TGF-beta 1 for 48 h. Basal T beta RII expression lev els were comparable in all five cell lines examined. In contrast, COLO-357 cells and BX-PC-3 cells expressed relatively high basal levels of T beta RI . However, COLO-357 cells harbored a normal Smad4 gene, whereas BX-PC-3 cel ls exhibited a complete deletion of this gene. We conclude that the TGF-bet a 1-induced T beta RII upregulation serves to enhance TGF-beta 1 responsive ness in COLO-357 cells, and that this upregulation requires the presence of adequate levels of T beta RI and T beta RII, and a functional Smad4 gene p roduct. Our findings also indicate that TGF-beta 1 may inhibit pancreatic c ancer cell growth via a Smad4-independent pathway.