Figure 9.

Model representing the signaling pathway of TRG-induced cellular effects in HCC cells . Incubation of the HCC cells with TRG in serum-containing media leads to a decrease in the expression of cyclin D1 resulting in cell growth arrest. TRG-induced reduction of cyclin D1 was shown to involve inhibition of CREB pathway in our earlier studies [32]. However, incubation with TRG under these conditions shows no apoptosis and leads to an increase in Akt^Ser473 and FoxO1^Thr24/3a^Thr32 phosphorylation involving PI3K and Pak pathways, which might lead to tumor progression. Inhibition of PI3K pathway but not Pak or Akt pathways sensitizes cells towards apoptosis. In addition, incubation with TRG in serum-deficient media antagonizes Akt^Ser473 phosphorylation and leads to potent apoptosis.