Immune modulating and anti-proliferative properties of STAT3 inhibitor piceatannol in hepatocellular carcinoma

Aims: Preliminary results from direct ex vivo flow cytometric analysis of peripheral blood from patients with hepatocellular carcinoma (HCC) revealed an immature phenotype and a substantial reduction of circulating dendritic cell (DC) subsets that was associated with increased IL–10 concentrations in serum and with tumor progression. It has been demonstrated that IL–10 exerts itrsquor;s biologic effect on eukaryotic cells by interacting with a specific cell surface receptor resulting in subsequent downstream engagement of the JAK-STAT signaling pathway and STAT3 activation. Moreover, constitutive STAT3 tyrosine or serine phosphorylation has been shown to possess transforming properties and to be strongly associated with tumor development and progression. Therefore, the aims of this project were to investigate 1) the influence of IL–10 on phenotype and migratory function of myeloid DC (MDC) in vitro; 2) whether piceatannol inhibits the effects of IL–10 on DC subsets in vitro; 3) whether STAT3 is constitutively activated in HCC cell lines and 4) whether piceatannol influences growth of HCC cell lines in vitro. Results: Our data revealed that peripheral blood mononuclear cells (PBMC) from healthy volunteers exposed to rhIL–10 showed a dramatic decrease of the MDC fraction that seemed to be related to the inhibition of DC differentiation from myeloid precursors within isolated PBMC. Moreover, IL–10 exposed MDC exhibited an immature phenotype and a propensity to migrate in response to inflammatory chemokines. However, the STAT3 inhibitor piceatannol was capable to protect MDC from IL–10 induced suppressive effects and to promote the development of MDC precursors from primitive stem cell progenitors. Moreover, the addition of piceatannol to IL–10-treated MDC induced a significant up-regulation of MHC class II expression, thus indicating an increase of maturation. Therefore, the STAT3 inhibitor piceatannol was capable to counteract the suppressive effects of IL–10 on MDC. In addition, we were able to show that STAT3 is constitutively activated in HCC cell lines and that STAT3 inhibition results in impaired proliferation and induction of apoptosis in these tumor cell lines in vitro. Conclusion: Our results indicate that piceatannol has immune modulating and anti-proliferative properties, and thus might be considered as a new adjuvant tool for the treatment of HCC patients.

HCC - Hepatocellular Carcinoma - Immune modulation - STAT3 inhibitor piceatannol