Gastric cancer (GC) is a lethal
malignancy and the second most common cause of
cancer-related deaths. Although treatment options such as
chemotherapy,
radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of
isorhamnetin (IH), a 3'-O-methylated metabolite of
quercetin on the
peroxisome proliferator-activated receptor γ (
PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of
PPAR-γ inhibitor. We found that IH increased
PPAR-γ activity and modulated the expression of
PPAR-γ regulated genes in GC cells. Also, the increase in
PPAR-γ activity was reversed in the presence of
PPAR-γ-specific inhibitor and a mutated
PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a
ligand of
PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the
ligand-binding pocket of
PPAR-γ that are reported to be critical for its activity and could competitively bind to
PPAR-γ. IH significantly increased the expression of
PPAR-γ in
tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the
PPAR-γ activation pathway in GC.