TGFβ-induced Smad signaling remains intact in primary human ovarian cancer cells

Disruptions in TGFbeta signaling have been implicated in various human cancers, including ovarian cancer. Our goal was to determine whether ovarian cancer cells isolated from patient ascites fluid were growth inhibited by TGFbeta1 treatment and further characterize the expression and activity profile of TGFbeta/Smad signaling components in human ovarian cancer cells. We found that 9 of 10 primary cultures of ovarian cancer cells (OC2-10) were growth inhibited by 16 pM TGFbeta1. One primary ovarian cancer sample (OC1) and the established ovarian cancer cell lines CaOV3 and SkOV3 continued to grow in the presence of TGFbeta1. All cells expressed components of the TGFbeta/Smad signaling pathway including TGFbeta1, TbetaRI, TbetaRII, Smad2, -3,-4, and Smad anchor for receptor activation. Although OC1, CaOV3, and SkOV3 are not growth inhibited by TGFbeta1, they can transmit the TGFbeta1 signal to turn on a transfected TGFbeta/Smad reporter gene, p3TP.lux. In addition, all cells up-regulate the endogenous TGFbeta target genes Smad7 and PAI-1. p15(Ink4B) mRNA is also up-regulated with TGFbeta1 treatment in OC2-9, whereas the p15(Ink4B) gene has been deleted in OC1, CaOV3, and SkOV3 cells. Homozygous deletion of p15(Ink4B) may account for TGFB resistance in some populations of ovarian cancer cells. Our data demonstrate that the TGFbeta/Smad signaling pathway remains functional in human ovarian cancer cells and suggest that if abnormalities exist in the cellular response of TGFbeta signals, they must lie downstream of the Smad proteins.