Transfection of the type I TGF-beta receptor restores TGF-beta responsiveness in pancreatic cancer.

Transforming growth factor-beta (TGF-beta) signaling is initiated following heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I TGF-beta receptor (TbetaRI). Both receptors are required for TGF-beta responsiveness. In the present study, we characterized the actions of TGF-beta1 in T3M4 human pancreatic cancer cells, which express low levels of TbetaRI and high levels of TbetaRII. Cells were transiently transfected with p3TP-Lux, a TGF-beta-responsive luciferase reporter gene construct. TGF-beta1 was without effect in parental T3M4 cells, but caused a time- and dose-dependent increase in luciferase activity in T3M4 cells co-transfected with a TbetaRI cDNA expression vector. Co-transfection of TbetaRI with a truncated Smad4 cDNA that is known to block TGF-beta-dependent signaling, abrogated the TbetaRI-induced increase in luciferase activity. Sequencing of the TbetaRI and the Smad4 genes in T3M4 cells did not reveal any mutations. These findings indicate that one mechanism for TGF-beta resistance in pancreatic cancer is due to a quantitative decrease in TbetaRI expression.