Quercetin and EGCG Exhibit Chemopreventive Effects in Cholangiocarcinoma Cells via Suppression of JAK/STAT Signaling Pathway

Quercetin and epigallocatechin-3-gallate (EGCG) are dietary phytochemicals with antiinflammatory and antitumor effects. In the present study, we examined the effects of these two compounds on Janus-like kinase (JAK)/signal transduction and transcription (STAT) pathway of cholangiocarcinoma (CCA) cells, because CCA is one of the aggressive cancers with very poor prognosis and JAK/STAT pathway is critically important in inflammation and carcinogenesis. The results showed that the JAK/STAT pathway activation by proinflammatory cytokine interleukin-6 and interferon-γ in CCA cells was suppressed by pretreatment with quercetin and EGCG, evidently by a decrease of the elevated phosphorylated-STAT1 and STAT3 proteins in a dose-dependent manner. The cytokine-mediated up-regulation of inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) via JAK/STAT cascade was abolished by both quercetin and EGCG pretreatment. Moreover, these flavonoids also could inhibit growth and cytokine-induced migration of CCA cells. Pretreatment with specific JAK inhibitors, AG490 and piceatannol, abolished cytokine-induced iNOS and ICAM-1 expression. These results demonstrate beneficial effects of quercetin and EGCG in the suppression of JAK/STAT cascade of CCA cells. Quercetin and EGCG would be potentially useful as cancer chemopreventive agents against CCA.