Int J Oncol, 2013 May 1
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.
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