Quercetin induces proteolysis of mesenchymal marker vimentin through activation of caspase-3, and decreases cancer stem cell population in human papillary thyroid cancer cell line.

Abstract

Back groundEpithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play an essential role in metastasis of papillary thyroid cancer (PTC), and vimentin is associated with lymph node metastasis and poor prognosis. Hence, inhibition of EMT and effective elimination of CSCs offers a novel target for developing new therapeutic agents. The objective of this study is to inspect the effect of quercetin, a major dietary bioactive flavonoid, on vimentin, CSCs and associated mechanism. MethodsThe first mechanism of quercetin mediated cytotoxicity was investigated in NPA cell line. Subsequently, the effect of quercetin was investigated on glycolysis, vimentin, CSCs, and the mechanism of vimentin degradation was also explored. ResultQuercetin effectively induces cytotoxicity by executing intrinsic apoptosis and activates caspase-3 through extracellular signal-regulated kinase (ERK) activation in NPA cell line having typical mesenchymal characters. Quercetin inhibits NPA cells migration and reduces extracellular acidification rate (ECAR), an indicator of enhanced glycolysis, required for cell migration. Quercetin treatment suppresses vimentin phosphorylation at lower concentrations, a critical step in cell migration, further proving its potential against cell migration. Phosphorylation of Vimentin is also crucial in the protection of vimentin from caspase-mediated proteolysis. Interestingly, quercetin activates caspase-3 at higher concentrations; hence, total vimentin levels were investigated, and caspase-3 mediated proteolysis of vimentin was observed. Vimentin and glycolysis are essential features of the mesenchymal state, which is required to maintain CSCs. Ours data also suggests quercetin mediated reduction in CSCs population. ConclusionWe report a novel mechanism of quercetin mediated inhibition of NPA cells migration by suppressing vimentin phosphorylation and subsequent proteolysis. Collectively our data suggest the potential of quercetin as an innovative anti-cancer therapeutic agent for PTC management.