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Anomalies of the TGF-beta postreceptor signaling pathway in ovarian cancer cell lines
1Section of Gynecologic and Medical Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. weihu@notes.mdacc.tmc.edu
Abstract:
Transforming growth factor-beta (TGF-beta) can cause cell cycle arrest, terminal differentiation, or apoptosis in most normal epithelial cells, whereas most malignant cell lines are resistant to TGF-beta. Mechanisms of resistance to TGF-beta caused by modulation of cell cycle regulators and/or inactivation of components of the TGF-beta signaling transduction pathway such as C-myc and Smad4 have been demonstrated in human pancreatic cancer and squamous cell carcinoma cell lines. But, this has not been shown in ovarian cancer. To investigate the potential association between loss of sensitivity to TGF-beta and expression status of transforming growth factor receptor II (T beta RII), Smad4, CDC25A and C-myc in fourteen cell lines derived from ovarian cancer, 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. Expression of Smad4 was decreased in ten cell lines and nine cell lines overexpressed 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 not overexpressed in any of these cell lines. The loss of sensitivity to TGF-beta of cell lines derived from ovarian cancers may be related to (1) a decreased expression of Smad4, which mediates TGF-beta induced growth inhibition; and/or (2) an overexpression of CDC25A. This overexpression correlates with increased tumorigenicity of ovarian cancer cell lines. The loss of sensitivity to TGF-beta is not associated with a lack of T beta RII.
Insights
Ovarian cancer cells resistant to TGF-beta may be due to decreased Smad4 or increased CDC25A. This resistance is not linked to transforming growth factor receptor II (T beta RII) levels.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Transforming growth factor-beta (TGF-beta) typically induces cell cycle arrest in normal epithelial cells, but malignant cells often exhibit resistance.
- Mechanisms of TGF-beta resistance, involving cell cycle regulators and signaling pathways like C-myc and Smad4, are known in other cancers but not well-established in ovarian cancer.
Purpose of the Study:
- To investigate the relationship between TGF-beta insensitivity and the expression of transforming growth factor receptor II (T beta RII), Smad4, CDC25A, and C-myc in ovarian cancer cell lines.
Main Methods:
- Semi-quantitative RT-PCR was used to examine gene expression levels in fourteen ovarian cancer cell lines.
- Normal ovarian surface tissues served as controls.
- Tumorigenicity was assessed via xenografts in nude mice.
Main Results:
- T beta RII expression was present in all tested cell lines.
- Smad4 expression was decreased in ten cell lines, and CDC25A was overexpressed in nine.
- CDC25A overexpression was significantly higher in tumorigenic (88%) versus non-tumorigenic (20%) ovarian cancer cell lines (P < 0.05). C-myc was not overexpressed.
Conclusions:
- Loss of TGF-beta sensitivity in ovarian cancer may stem from reduced Smad4 expression or elevated CDC25A levels.
- CDC25A overexpression correlates with increased ovarian cancer cell tumorigenicity.
- Insensitivity to TGF-beta in ovarian cancer is not associated with a deficiency in T beta RII expression.