Anomalies of the TGF-beta postreceptor signaling pathway in ovarian cancercell lines

Transforming growth factor-beta (TGF-beta) can cause cell cycle arrest, ter minal differentiation, ol apoptosis in most normal epithelial cells, wherea s most malignant cell lines are resistant to TGF-beta. Mechanisms of resist ance to TGF-beta caused by modulation of cell cycle regulators and/or inact ivation of components of the TGF-beta signaling transduction pathway such a s C-myc and Smad4 have been demonstrated in human Pancreatic cancer and squ amous cell cat-cinema cell lines. But, this has not been shown in ovarian c ancer: To investigate the potential association between loss of sensitivity to TGF-beta and expression status of transforming growth factor receptor I I (T beta RII), Smad4, CDC25A and C-myc in fourteen cell lines derived from ovarian cancel; the expression levels of these genes were examined by semi -quantitative RT-PCR. Normal ovarian surface tissues were used as controls. Expression of T beta RII was detectable in all of fourteen cell lines. Exp ression of Smad4 was decreased in ten cell lines and nine cell lines over e xpressed CDC25A, compared to normal controls. CDC25A gene was overexpressed in 88% (8/9) of tumorigenic cell lines as determined by xenografts in nude mice, and only in 20% (1/5) of non-tumorigenic cell lines (P<0.05). C-myc was nor over expressed in arty of these cell lines. The loss of sensitivity to TGF-beta of cell lines derived from ovarian cancers may be related to ( I) a decreased expression of Smad4, which mediates TGF-beta induced growth inhibition; and/or (2) an overexpression of CDC25A. This overexpression con elates with increased tumor igenicity of ovarian cancer cell lines. The lo ss of sensitivity to TGF-beta is not associated with a lack of T beta RII.