title: 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor γ (PPARγ).
abstract: 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.
authors.affiliation: School of Postgraduate Studies and Research, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia.
authors.forename: Boon Shing
authors.initials: BS
authors.lastname: Tan
authors.forename: Owen
authors.initials: O
authors.lastname: Kang
authors.forename: Chun Wai
authors.initials: CW
authors.lastname: Mai
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.forename: Alan Soo-Beng
authors.initials: AS
authors.lastname: Khoo
authors.forename: Mallikarjuna Rao
authors.initials: MR
authors.lastname: Pichika
authors.forename: Tracey D
authors.initials: TD
authors.lastname: Bradshaw
authors.forename: Chee-Onn
authors.initials: CO
authors.lastname: Leong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D000970:Antineoplastic Agents; D002396:Catechols; D008024:Ligands; D016328:NF-kappa B; D047495:PPAR gamma; C040115:shogaol; D015230:Prostaglandin D2