A Food Odorant, α‐Ionone, Inhibits Skin Cancer Tumorigenesis by Activation of OR10A6

Scope This study aims to investigate the anticancer properties of α‐ionone in squamous cell carcinoma (SCC). Methods and results The expression of OR10A6 together with olfactory receptor signaling components is demonstrated in A431 human SCC cells via RT‐PCR and qRT‐PCR analysis. OR10A6 activation in A431 cells using the ligand α‐ionone inhibits proliferation and migration but induces apoptosis which is confirmed by proliferation assay, colony formation, and western blotting. The mechanism involves the core proteins of the Hippo pathway, where the phosphorylation of large tumor suppressor kinase (LATS), yes‐associated protein (YAP), and transcriptional coactivator with PDZ‐binding motif (TAZ) is confirmed by western blotting. However, the anticancer effects of α‐ionone are abrogated in A431 cells with OR10A6 gene knockdown. In A431 xenograft mouse model, the injection of α‐ionone suppresses tumor growth, induces apoptosis, and increases phosphorylation of the LATS‐YAP‐TAZ signaling axis in the Hippo pathway. None of these effects are observed in xenografted tumors with OR10A6 gene knockdown. Conclusion These findings collectively demonstrate that activation of ectopic OR OR10A6 by α‐ionone in SCC cells stimulates the Hippo pathway and suppresses tumorigenesis both in vitro and in vivo, suggesting a novel therapeutic candidate for the treatment of SCC.