Liver
tumor cells show several molecular alterations which favor pro-survival signaling. Among those, we have proposed the
NADPH oxidase NOX1 as a prosurvival signal for liver
tumor cells. On the one side, we have described that FaO rat
hepatoma cells show NOX1-dependent partial resistance to apoptosis induced by
Transforming Growth Factor beta (TGF-β). On the other side, we have shown that FaO cells, as well as different human
hepatocellular carcinoma (HCC) cell lines, are able to proliferate in the absence of serum through the activation of a NOX1-dependent signaling pathway. The aim of this work was to analyze the effects of
NADPH oxidase pharmacological inhibition in liver
tumor cells using the inhibitor
VAS2870. This compound inhibits dose-dependently autocrine increase of cell number in FaO rat
hepatoma cells, and almost completely blocked ROS production and
thymidine incorporation when used at 25μM. Such inhibitory effect on autocrine growth is coincident with lower
mRNA levels of EGFR (
Epidermal Growth Factor Receptor) and its
ligand TGF-α (
Transforming Growth Factor-alpha), and decreased phosphorylation of the EGFR itself and other downstream targets, such as SRC or AKT. Moreover,
NADPH oxidase pharmacological inhibition also effectively attenuates serum-dependent growth and phosphorylation of AKT and ERK. Importantly, these inhibitory effects on either autocrine or serum-dependent cell growth are observed in several human HCC cell lines. Finally, we have observed that
VAS2870 is also effective in enhancing apoptosis induced by a physiological stimulus, such as TGF-β. In summary,
NADPH oxidase pharmacological inhibition could be considered a promising tool in the treatment of
liver cancer.