Transforming growth factor-beta (TGF beta) is involved in the regulation of
liver cell proliferation and apoptosis, and escape of hepatoma cells from
the growth restraining signals of TGF beta has been suggested to contribute
to tumor development. TGF beta modulates gene transcription by receptor-me
diated activation of Smad proteins which act as transcription factors. TGF
beta -mediated primary signaling responses as well as effects on the cell c
ycle and apoptosis were investigated in the human hepatoblastoma line HepG2
, the rat hepatoma line FTO-2B and the mouse hepatoma line 55.1c, Activatio
n of a Smad (Sma and Mad homolog) response-element-driven luciferase report
er by TGF beta was very similar in ail three cell lines, indicating functio
nality of the primary TGF beta signaling pathway. Moreover, TGF beta -induc
ible early gene was transiently activated by TGF beta in all cell lines as
shown by RT-PCR, HepG2 cells, however, were completely resistant to TGF bet
a -induced growth arrest and apoptosis and 55.1c cells were only slightly s
usceptible to TGF beta -induced apoptosis, By contrast, treatment of FTO-2B
cells with TGF beta led to a partial G(0)/G(1) arrest and a strong inducti
on of apoptosis, TGF beta -induced apoptosis of FTO-2B cells was inhibited
by dexamethasone, insulin, phenobarbital and dieldrin, Of these agents, onl
y insulin led to a significant reduction of TGF beta -stimulated Smad-repor
ter activity, suggesting that the other compounds interfere with TGF beta -
induced apoptosis downstream of Smad-mediated primary transcriptional respo
nses at a level that may be constitutively altered in apoptosis-resistant h
epatoma cell lines.