Ovarian carcinoma cell cultures are resistant to TGF-beta1-mediated growth inhibition despite expression of functional receptors

Gynecol Oncol. 1999 Oct;75(1):72-7. doi: 10.1006/gyno.1999.5535.


Objective: The purpose of this study was to determine the response of ovarian carcinoma cells to TGF-beta1 and to examine components of the TGF-beta signaling pathway.

Methods: Twenty-three primary ovarian cancer cell (CSOC) cultures established from solid ovarian carcinomas were treated with TGF-beta1 and assayed for growth response by MTT assay. Expression of TGF-beta receptor I (TbetaR-I) and receptor II (TbetaR-II), essential for effective signaling, was determined by Western analysis of CSOC cultures. TGF-beta1 ligand-induced phosphorylation of TbetaR-I was determined by immunoprecipitation of TbetaR-I followed by a protein kinase assay to assess TbetaR-I phosphorylation, an essential first step in TGF-beta signal transduction. Gelatin zymography performed on 5 CSOC cultures incubated with TGF-beta1 was used to determine TGF-beta's effect on matrix metalloproteinase production. Normal ovarian surface epithelial cells were used for comparison.

Results: Eighteen of twenty-three (78%) CSOC cultures demonstrated no significant growth inhibition in response to TGF-beta1 treatment. All cell cultures expressed TbetaR-I and TbetaR-II and exhibited TbetaR-I phosphorylation following TGF-beta1 treatment. CSOC cultures produced significantly higher levels of matrix metalloproteinase-2 (MMP-2) than normal ovarian surface epithelial cells; however, the level of MMP-2 expression was not regulated by TGF-beta1.

Conclusion: These results indicate that TGF-beta1 resistance and higher levels of MMP-2 production may be inherent properties of the ovarian cancer phenotype. The initial steps in the TGF-beta signaling pathway, receptor expression, ligand binding, and TbetaR-I phosphorylation, appear to be functional in primary ovarian cancer cell cultures. Therefore, the mechanism of growth resistance is downstream of TbetaR-I phosphorylation.

MeSH terms

  • Cell Division
  • Drug Resistance, Neoplasm
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Metalloendopeptidases / metabolism
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Phosphorylation
  • Receptors, Transforming Growth Factor beta / biosynthesis
  • Receptors, Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / therapeutic use*
  • Tumor Cells, Cultured


  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • Metalloendopeptidases