TRANSFECTION OF THE TYPE-I TGF-BETA RECEPTOR RESTORES TGF-BETA RESPONSIVENESS IN PANCREATIC-CANCER

Transforming growth factor-beta (TGF-P) signaling is initiated followi ng heterodimerization of the type II TGF-P receptor (T beta RII) with the type I TGF-beta receptor (T beta RI). Both receptors are required for TGF-beta responsiveness. In the present study, we characterized th e actions of TGF-beta I in T3M4 human pancreatic cancer cells, which e xpress low levels of T beta RI and high levels of T beta RII. Cells we re transiently transfected with p3TP-Lux, a TGF-beta-responsive lucife rase reporter gene construct. TGF-beta I was without effect in parenta l T3M4 cells, but caused a time- and dose-dependent increase in lucife rase activity in T3M4 cells co-transfected with a T beta RI cDNA expre ssion vector. Co transfection of T beta RI with a truncated Smad4 cDNA that is known to block TGF-beta-dependent signaling, abrogated the T beta RI-induced in crease in luciferase activity. Sequencing of the T beta RI and the Smad4 genes in T3M4 cells did not reveal any mutations . These findings indicate that one mechanism for TGF-beta resistance i n pancreatic cancer is due to a quantitative decrease in T beta RI exp ression. (C) 1998 Wiley-Liss, Inc.