Structurally related odorant ligands of the olfactory receptor OR51E2 differentially promote metastasis emergence and tumor growth

Olfactory receptors are G protein-coupled receptors. Some of them are expressed in tumor cells, such as the OR51E2 receptor overexpressed in LNCaP prostate cancer cells. It is considered a prostate tumor marker. We previously demonstrated that this receptor is able to promote LNCaP cell invasiveness in vitro upon stimulation with its odorant agonist beta-ionone, leading to increased generation of metastases in vivo. In the present study, we show that even a relatively short exposure to beta-ionone is sufficient to promote metastasis emergence. Moreover, alpha-ionone, considered an OR51E2 antagonist, in fact promotes prostate tumor growth in vivo. The combination of alpha-ionone with beta-ionone triggers a higher increase in the total tumor burden than each molecule alone. To support the in vivo results, we demonstrate in vitro that alpha-ionone is a real agonist of OR51E2, mainly sustaining LNCaP cell growth, while beta-ionone mainly promotes cell invasiveness. So, while structurally close, alpha-ionone and beta-ionone appear to induce different cellular effects, both leading to increased tumor aggressiveness. This behaviour could be explained by a different coupling to downstream effectors, as it has been reported for the so-called biased ligands of other G protein-coupled receptors