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Carcinogenesis, Vol. 22, No. 3, 447-452, March 2001
© 2001 Oxford University Press

CARCINOGENESIS

Transforming growth factor-ß1-induced Smad signaling, cell-cycle arrest and apoptosis in hepatoma cells

Christoph Lars Buenemann, Claudia Willy, Albrecht Buchmann, Alexander Schmiechen and Michael Schwarz,1

Institute of Toxicology, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany

Transforming growth factor-ß1 (TGFß) is involved in the regulation of liver cell proliferation and apoptosis, and escape of hepatoma cells from the growth restraining signals of TGFß has been suggested to contribute to tumor development. TGFß modulates gene transcription by receptor-mediated activation of Smad proteins which act as transcription factors. TGFß-mediated primary signaling responses as well as effects on the cell cycle and apoptosis were investigated in the human hepatoblastoma line HepG2, the rat hepatoma line FTO-2B and the mouse hepatoma line 55.1c. Activation of a Smad (Sma and Mad homolog) response-element-driven luciferase reporter by TGFß was very similar in all three cell lines, indicating functionality of the primary TGFß signaling pathway. Moreover, TGFß-inducible early gene was transiently activated by TGFß in all cell lines as shown by RT–PCR. HepG2 cells, however, were completely resistant to TGFß-induced growth arrest and apoptosis and 55.1c cells were only slightly susceptible to TGFß-induced apoptosis. By contrast, treatment of FTO-2B cells with TGFß led to a partial G0/G1 arrest and a strong induction of apoptosis. TGFß-induced apoptosis of FTO-2B cells was inhibited by dexamethasone, insulin, phenobarbital and dieldrin. Of these agents, only insulin led to a significant reduction of TGFß-stimulated Smad-reporter activity, suggesting that the other compounds interfere with TGFß-induced apoptosis downstream of Smad-mediated primary transcriptional responses at a level that may be constitutively altered in apoptosis-resistant hepatoma cell lines.


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