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β-Ionone suppresses colorectal tumorigenesis by activating OR51E2, a potential tumor suppressor
Ji-Sun Kim1, Sungyun Cho2, Mi-Young Jeong1
1Department of Biotechnology, Graduate school of Biotechnology, Korea University, Seoul 02841, South Korea.
Background:
Olfactory receptors (ORs) are present in non-olfactory tissues and contribute to diverse biological roles beyond smell perception. Among them, OR51E2 has been associated with cancer biology, and its activator, β-ionone, a natural terpenoid, is known to have anticancer effects.
Purpose:
This study aimed to clarify the tumor-suppressive role of OR51E2 in colorectal cancer (CRC), unravel the regulatory mechanism underlying its downregulation, and evaluate the therapeutic potential of β-ionone, an OR51E2 ligand, in CRC progression.
Study Design And Methods:
OR51E2 expression was analyzed in human CRC tissues, matched adjacent normal tissues, and cell lines. The involvement of N6-methyladenosine (m6A) modification of OR51E2 mRNA stability was examined using METTL3/14 and YTHDF1/2/3 knockdown experiments. β-Ionone-mediated effects on intracellular calcium signaling, cell proliferation, migration, and apoptosis were evaluated in an OR51E2-dependent manner. The therapeutic efficacy of β-ionone was further evaluated in vivo using a xenograft model in nude mice.
Results:
OR51E2 mRNA expression and immunoreactivity were significantly reduced in CRC cells and tissues due to decreased mRNA stability. Knockdown of METTL3/14 or YTHDF1/2/3 increased OR51E2 mRNA and protein expression and inhibited CRC cell proliferation. Treatment with STM2457, an METTL3 inhibitor, restored OR51E2 expression and suppressed CRC cell proliferation. β-Ionone, a ligand of OR51E2, increased intracellular calcium levels, decreased MEK/ERK phosphorylation, and inhibited CRC cell proliferation while inducing apoptosis. These effects were abolished in OR51E2 knockdown cells. In a xenograft model, β-ionone administration (5 and 10 mg/kg body weight) significantly reduced tumor growth.
Conclusion:
This study identifies m6A modification as a critical mechanism underlying the downregulation of OR51E2 in CRC. Activation of OR51E2 by β-ionone suppresses CRC cell proliferation and induces apoptosis by elevating intracellular calcium levels, which inhibits the MEK-ERK pathway. These findings highlight OR51E2 as a potential therapeutic target and suggest that β-ionone or m6A inhibition may represent novel strategies for CRC treatment.
Insights
Olfactory receptor OR51E2 is downregulated in colorectal cancer (CRC) due to m6A modification. Its activator, beta-ionone, suppresses CRC by targeting the MEK-ERK pathway, offering a potential therapeutic strategy.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- Olfactory receptors (ORs) have roles beyond olfaction, including in cancer biology.
- OR51E2 is implicated in cancer, with its activator, beta-ionone, showing anticancer effects.
Purpose of the Study:
- To investigate the tumor-suppressive role of OR51E2 in colorectal cancer (CRC).
- To elucidate the mechanism of OR51E2 downregulation in CRC.
- To assess the therapeutic potential of beta-ionone for CRC.
Main Methods:
- Analyzed OR51E2 expression in CRC tissues and cell lines.
- Investigated N6-methyladenosine (m6A) modification's role in OR51E2 mRNA stability using knockdown experiments.
- Evaluated beta-ionone's effects on CRC cells and in a xenograft model.
Main Results:
- OR51E2 expression was reduced in CRC due to decreased mRNA stability, influenced by m6A modification.
- Beta-ionone treatment suppressed CRC cell proliferation and induced apoptosis via OR51E2 activation and MEK/ERK pathway inhibition.
- Beta-ionone reduced tumor growth in a xenograft model.
Conclusions:
- m6A modification critically downregulates OR51E2 in CRC.
- Beta-ionone activates OR51E2, suppressing CRC via calcium signaling and MEK-ERK inhibition.
- OR51E2 and beta-ionone represent potential therapeutic targets for CRC.
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