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TGFß-Induced Smad Signaling Remains Intact in Primary Human Ovarian Cancer Cells

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7

Address all correspondence and requests for reprints to: Mark W. Nachtigal, Dalhousie University, Department of Pharmacology, Tupper Medical Building, Halifax, Nova Scotia, Canada B3H 4H7. E-mail: . mnachtig{at}is.dal.ca

Disruptions in TGFß 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 TGFß1 treatment and further characterize the expression and activity profile of TGFß/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 TGFß1. One primary ovarian cancer sample (OC1) and the established ovarian cancer cell lines CaOV3 and SkOV3 continued to grow in the presence of TGFß1. All cells expressed components of the TGFß/Smad signaling pathway including TGFß1, TßRI, TßRII, Smad2, -3, -4, and Smad anchor for receptor activation. Although OC1, CaOV3, and SkOV3 are not growth inhibited by TGFß1, they can transmit the TGFß1 signal to turn on a transfected TGFß/Smad reporter gene, p3TP.lux. In addition, all cells up-regulate the endogenous TGFß target genes Smad7 and PAI-1. p15^Ink4B mRNA is also up-regulated with TGFß1 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 TGFß resistance in some populations of ovarian cancer cells. Our data demonstrate that the TGFß/Smad signaling pathway remains functional in human ovarian cancer cells and suggest that if abnormalities exist in the cellular response of TGFß signals, they must lie downstream of the Smad proteins.

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