Tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) selectively kills various types of
cancer cells without harming normal cells, but TRAIL resistance has been frequently observed in
cancer cells.
Propolis (
bee glue) is a material collected from various plants by honeybees and is a rich source of bioactive compounds, including the natural
flavonoid chrysin, which possesses multiple anticancer effects. We investigated the mechanism underlying the TRAIL sensitization effect of
chrysin, which is a major constituent of Thai
propolis, in human lung and
cervical cancer cell lines.
Propolis extract and
chrysin sensitizes A549 and HeLa human
cancer cell lines to TRAIL-induced apoptosis. The TRAIL sensitization effect of
chrysin is not mediated by inhibition of TRAIL-induced NF-κB activation or by
glutathione depletion. Immunoblot analysis using a panel of
anti-apoptotic proteins revealed that
chrysin selectively decreases the levels of Mcl-1
protein, by downregulating Mcl-1 gene expression as determined by qRT-PCR. The contribution of Mcl-1 in TRAIL resistance was confirmed by si-Mcl-1 knockdown. Among signaling pathways that regulate Mcl-1 gene expression, only constitutive STAT3 phosphorylation was suppressed by
chrysin. The proposed action of
chrysin in TRAIL sensitization by inhibiting STAT3 and downregulating Mcl-1 was supported by using a STAT3‑specific inhibitor,
cucurbitacin-I, which decreased Mcl-1 levels and enhanced TRAIL-induced cell death, similar to that observed with
chrysin treatment. In conclusion, we show the potential of
chrysin in overcoming TRAIL resistance of
cancer cells and elucidate its mechanism of action.