6-Shogaol has been shown to possess many antitumor properties including inhibition of
cancer cell growth, inhibition of
cancer metastasis, induction of apoptosis in
cancer cells and induction of
cancer cell differentiation. Despite its prominent antitumor effects, the direct molecular target of
6-shogaol has remained elusive. To identify the direct targets of
6-shogaol, a comprehensive antitumor profile of
6-shogaol (NSC752389) was tested in the NCI-60 cell line in an in vitro screen. The results show that
6-shogaol is COMPARE negative suggesting that it functions via a mechanism of action distinct from existing classes of therapeutic agents. Further analysis using microarray gene profiling and Connectivity Map analysis showed that MCF-7 cells treated with
6-shogaol display gene expression signatures characteristic of
peroxisome proliferator activated receptor γ (PPARγ) agonists, suggesting that
6-shogaol may activate the PPARγ signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with
6-shogaol induced PPARγ transcriptional activity, suppressed NFκB activity, and induced apoptosis in breast and
colon cancer cells in a PPARγ-dependent manner. Furthermore,
6-shogaol is capable of binding to PPARγ with a binding affinity comparable to 15-delta
prostaglandin J2, a natural
ligand for PPARγ. Together, our findings suggest that the antitumor effects of
6-shogaol are mediated through activation of PPARγ and imply that activation of PPARγ might be beneficial for breast and
colon cancer treatment.