1 research outputs found
Scopadulciol, Isolated from <i>Scoparia dulcis</i>, Induces β‑Catenin Degradation and Overcomes Tumor Necrosis Factor-Related Apoptosis Ligand Resistance in AGS Human Gastric Adenocarcinoma Cells
Scopadulciol
(<b>1</b>), a scopadulan-type diterpenoid, was isolated from <i>Scoparia dulcis</i> along with three other compounds (<b>2</b>–<b>4</b>) by an activity-guided approach using
the TCF reporter (TOP) luciferase-based assay system. A fluorometric
microculture cytotoxicity assay (FMCA) revealed that compound <b>1</b> was cytotoxic to AGS human gastric adenocarcinoma cells.
The treatment of AGS cells with <b>1</b> decreased β-catenin
levels and also inhibited its nuclear localization. The pretreatment
of AGS cells with a proteasome inhibitor, either MG132 or epoxomicin,
protected against the degradation of β-catenin induced by <b>1</b>. The <b>1</b>-induced degradation of β-catenin
was also abrogated in the presence of pifithrin-α, an inhibitor
of p53 transcriptional activity. Compound <b>1</b> inhibited
TOP activity in AGS cells and downregulated the protein levels of
cyclin D1, c-myc, and survivin. Compound <b>1</b> also sensitized
AGS cells to tumor necrosis factor-related apoptosis ligand (TRAIL)-induced
apoptosis by increasing the levels of the death receptors, DR4 and
DR5, and decreasing the level of the antiapoptotic protein Bcl-2.
Collectively, our results demonstrated that <b>1</b> induced
the p53- and proteasome-dependent degradation of β-catenin,
which resulted in the inhibition of TCF/β-catenin transcription
in AGS cells. Furthermore, <b>1</b> enhanced apoptosis in TRAIL-resistant
AGS when combined with TRAIL