Selected Article of Journal (IMR)

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 c (PPARc) agonists, suggesting that 6-shogaol may activate the PPARc signaling pathway for its antitumor effects. Indeed, treatment of MCF-7 and HT29 cells with 6-shogaol induced PPARc transcriptional activity, suppressed NFjB activity, and induced apoptosis in breast and colon cancer cells in a PPARc-dependent manner. Furthermore, 6-shogaol is capable of binding to PPARc with a binding affinity comparable to 15-delta prostaglandin J2, a natural ligand for PPARc. Together, our findings suggest that the antitumor effects of 6-shogaol are mediated through activation of PPARc and imply that activation of PPARc might be beneficial for breast and colon cancer treatment.