Monoterpene (−)-citronellal affects hepatocarcinoma cell signaling via an olfactory receptor

• Monoterpenes increase intracellular Ca2+ levels in Huh7 cells.
• (−)-Citronellal induces cAMP-dependent Ca2+ increases in Huh7 cells via OR1A2.
• OR1A2 activation results in MAPK phosphorylation and reduced cell proliferation.
• OR1A2 as a molecular sensor for monoterpenes in Huh7 cells.
• ORs provide novel therapeutic targets for hepatocellular cancer treatment.

Terpenes are the major constituents of essential oils in plants. In recent years, terpenes have become of clinical relevance due to their ability to suppress cancer development. Their effect on cellular proliferation has made them promising agents in the prevention or treatment of many types of cancer. In the present study, a subset of different monoterpenes was investigated for their molecular effects on the hepatocellular carcinoma cell line Huh7. Using fluorometric calcium imaging, acyclic monoterpene (−)-citronellal was found to induce transient Ca2+ signals in Huh7 cells by activating a cAMP-dependent signaling pathway. Moreover, we detected the (−)-citronellal-activated human olfactory receptor OR1A2 at the mRNA and protein levels and demonstrated its potential involvement in (−)-citronellal-induced calcium signaling in Huh7 cells. Furthermore, activation of OR1A2 results in phosphorylation of p38 MAPK and reduced cell proliferation, indicating an effect on hepatocellular carcinoma progression. Here, we provide for the first time data on the molecular mechanism evoked by (−)-citronellal in human hepatocellular carcinoma cells. The identified olfactory receptor could serve as a potential therapeutic target for cancer diagnosis and treatment.